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(The FASEB Journal. 2005;19:161-169.)
© 2005 FASEB

The wild-type Ras: road ahead

Arvind Singh, A. Pavani Sowjanya and Gayatri Ramakrishna1

Centre for DNA Fingerprinting and Diagnostics, Nacharam, Hyderabad, Andhra Pradesh, India

1Correspondence: Centre for DNA Fingerprinting and Diagnostics, ECIL Road, Nacharam, Hyderabad-500076, Andhra Pradesh, India. E-mail: gayatri{at}cdfd.org.in


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 DIVERSE ROLES OF WILD-TYPE...
 GROWTH-SUPPRESSIVE NATURE OF...
 IS WILD-TYPE RAS AN...
 ROLE OF WILD-TYPE RAS-GDP
 ROLE OF WILD-TYPE RAS-GTP
 WILD-TYPE VS. ONCOGENIC RAS
 CONCLUSIONS
 REFERENCES
 
The cellular Ras is known to play an important role in cellular proliferation mediated by growth factor receptor. Evidence also points to its role in growth arrest. Substantiated proof for growth-suppressive activity of wild-type Ras comes from studies that showed 1) loss of wild-type ras allele in tumors, 2) suppression of growth in cells transformed by oncogenic ras upon overexpression of wild-type Ras, and 3) up-regulation of Ras expression during postnatal development and following growth arrest of untransformed cells in culture. To understand the mechanism by which the wild-type Ras brings about these diverse actions, we evaluated its well-known role in actively proliferating cells and its less understood role in growth arrest. This led to the proposal that wild-type Ras in either GDP or GTP-bound state can antagonize the function of oncogenic Ras.—Singh, A., Sowjanya, A. P., Ramakrishna, G. The wild-type Ras: road ahead.


Key Words: Ras-GDP • Ras-GTP • mutant ras • cyclin-dependent kinase inhibitors (CDKIs)


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
DIVERSE ROLES OF WILD-TYPE...
 GROWTH-SUPPRESSIVE NATURE OF...
 IS WILD-TYPE RAS AN...
 ROLE OF WILD-TYPE RAS-GDP
 ROLE OF WILD-TYPE RAS-GTP
 WILD-TYPE VS. ONCOGENIC RAS
 CONCLUSIONS
 REFERENCES
 
EVEN AFTER two decades of discovery, the Ras family of proteins, which are small GTPases, attracts attention because of the key role in signaling and tumorigenesis. Ras-mediated signaling involves a plethora of cellular targets that can preferentially interact with individual ras isoforms involving extensive cross-talk. This in turn leads to execution of wide-ranging cellular responses such as proliferation, senescence, apoptosis, and differentiation. Nearly all available information today on ras emphasizes its oncogenic form. Even the extensive literature available on ras falls short with regard to differences in signaling events, if any, mediated by wild-type and oncogenic ras. Information on wild-type ras focuses on its role in cell cycle execution, but evidence also points to its tumor-suppressive activity (reviewed in refs 1 , 2 ). Ras-mediated signaling is becoming complex as ras isoforms show diverse responses depending on the species (rodent/human) and cell type (fibroblasts/epithelial and primary/immortalized cells) (3 , 4) . Therefore, it is of utmost importance to understand the role of wild-type rasvis-a-vis its oncogenic counterpart and differences in the signaling events they mediate in a particular cell type. In the present paper we discuss the diverse roles of wild-type Ras in cellular growth and oncosuppression.


   DIVERSE ROLES OF WILD-TYPE Ras
TOP
 ABSTRACT
 INTRODUCTION
 DIVERSE ROLES OF WILD-TYPE...
GROWTH-SUPPRESSIVE NATURE OF...
 IS WILD-TYPE RAS AN...
 ROLE OF WILD-TYPE RAS-GDP
 ROLE OF WILD-TYPE RAS-GTP
 WILD-TYPE VS. ONCOGENIC RAS
 CONCLUSIONS
 REFERENCES
 
The ability of Ras to bind the guanine nucleotides and cycle between the GDP- and GTP-bound state makes them ideal signal transducers (5) . With an incoming growth factor signal, the GDP molecule bound to Ras is exchanged with GTP, leading to activation of downstream targets. The wild-type Ras-GTP exists for only a short time because of the intrinsic GTPase activity, which in turn is enhanced by GTPase-activating protein (GAP). Compared with the wild-type Ras, the percentage of oncogenic Ras bound to GTP is strikingly higher because point mutation leads to lowering of GTP hydrolysis rate (Table 1 ).


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  		Table 1. Percentage of GTP/GDP bound Ras in NIH3T3 cellsa

The role of cellular Ras is best understood by either knocking out the gene or blocking its function. Different strategies employed suggest that wild-type ras can orchestrate such various functions such as cellular survival, proliferation, development, and immunity (Table 2 ). The following striking features emerge as to the role of wild-type ras in cellular proliferation: 1) not all ras isoforms are equally important in inducing proliferation in a given cell type, 2) in synchronized cells Ras is activated in early, mid-, and late G1 phases after growth factor stimulation, 3) in asynchronous cultures, Ras is active throughout the cell cycle phases, and 4) activated Ras overcomes the restriction point by modulating the levels of cyclin D1 and cyclin-dependent kinase inhibitor (CDKI) p27Kip in the fibroblasts (24 , 28 29 30 31) .


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  		Table 2. Experimental strategies used to understand the role of wild-type Ras

Besides its role in cellular proliferation, Ras plays a crucial role in differentiation of neuronal, myeloid, and adipocyte cells (32) . It has been reported that wild-type Ras protein is up-regulated in postnatal stages compared with the highly proliferative embryonic stages (33 34 35) . Further, its level and activity goes up with increasing cell confluency (36 37 38) . These reports suggest an association between Ras expression and growth arrest/differentiation. The mechanism by which cellular Ras maintains the differentiated state is still unclear.

Below we try to explain how wild-type Ras can bring about varied cellular responses depending on the cellular context, viz., proliferative vs. resting state. In contact inhibited cells, the endogenous Ras bound to GDP or GTP may be responsible for sustenance of differentiated/growth-arrested state and for induction of survival pathways to prevent apoptosis (Fig. 1 ). The fact that both wild-type Ras and N17Ras, existing predominantly in a GDP-bound state, can inhibit the oncogenic transformation is indicative of a role for the GDP-bound states of the protein (39 40 41 42 43 44 45) . In quiescent cells it is likely that Ras-GDP, by interacting with certain downstream targets, help in inducing CDKIs to maintain the growth-arrested state. This is supported by the observation that quiescent cells and fibroblasts transfected with N17Ras show induction of CDKI, p27Kip, thereby preventing the G1-S transition (24) . Up-regulation of Ras activity in confluent cells leads to the speculation that cellular contact, directly or indirectly, can bring about changes in the membrane leading to constitutive signaling by Ras for cellular survival. In contrast, an autocrine growth factor-mediated event in continuously cycling cells like stem cells, bone marrow, etc., may cause transient activation of cellular Ras leading to up-regulation of cyclin D1 or down-regulation of CDKIs, resulting in cell cycle progression. Future challenges will involve understanding the intricate mechanisms by which Ras-GDP/GTP can bring about the diverse cellular effects.



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  		Figure 1. Role of cellular Ras in dividing and nondividing cells. In dividing cells, transiently activated Ras may cause up-regulation of cyclin D1 or down-regulation of CDKIs, leading to cell cycle progression. In resting cells, Ras bound to GDP or GTP can 1) cause growth arrest or differentiation by up-regulating either the CDKIs or some unknown targets and/or 2) help in survival by preventing apoptosis.


   GROWTH-SUPPRESSIVE NATURE OF WILD-TYPE RAS
TOP
 ABSTRACT
 INTRODUCTION
 DIVERSE ROLES OF WILD-TYPE...
 GROWTH-SUPPRESSIVE NATURE OF...
IS WILD-TYPE RAS AN...
 ROLE OF WILD-TYPE RAS-GDP
 ROLE OF WILD-TYPE RAS-GTP
 WILD-TYPE VS. ONCOGENIC RAS
 CONCLUSIONS
 REFERENCES
 
The proto-oncogene Ras can also act as a tumor suppressor. Overexpression of wild-type K-, H-, and N-ras has been reported to reverse the transformed phenotype induced by their oncogenic counterparts (40 41 42 43) . All isoforms of the wild-type and oncogenic Ras can exert growth-suppressive activity in the myeloid leukemia cell K562, which incidentally carries no mutation in ras (44) . That wild-type Ras can suppress growth in the presence or absence of the oncogenic counterpart suggests that wild-type ras in general can have an anti-tumor action. K-ras null embryonic stem cells, when stably transfected with wild-type K-ras, induce smaller and more differentiated teratomas than those expressing the oncogenic ras, indicating the oncosuppressive role of the wild-type form (45) . Loss of wild-type ras or allelic imbalance at ras loci in animal tumors is suggestive of the oncosuppressive nature of wild-type ras (42 , 46 47 48) . Cancers of human origin, such as lung adenocarcinomas (49 , 50) , prostate cancer (51) , pancreatic cancer (52) , breast cancer (53) , and acute lymphoblastic leukemia (54) , showing loss of heterozygosity at the K-ras genetic locus provide additional evidence in favor of the tumor-suppressive role of wild-type Ras.

However, studies using the transgenic animal models show both tumor protective and promoting effects of wild-type ras (Table 3 ). These studies indicate that 1) wild-type N-ras can accentuate or suppress tumor formation depending on the cell type and carcinogen used, 2) loss of wild-type K-ras allele makes the animals more susceptible to tumor formation, and 3) in transgenic animals (K-raswild-type/oncogenic) expressing physiological levels of oncogenic Ras, the presence of coexisting wild-type ras allele is unable to suppress tumor transformation, at least in certain cell types. The disparate effects of wild-type ras on tumor suppression when using transgenic animals have been summarized by Diaz et al. (61) . Since only certain cell types show tumor formation in the ras knock-in transgenic mice, it is clear that tissue/cellular specificity determines the tumor-promoting or protective role of wild-type Ras. Thus, depending on the cellular context, a sophisticated cellular mechanism exists that decides the final outcome of the wild-type Ras.


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  		Table 3. Diverse effects of wild-type Ras in transgenic mice with different genetic backgroundsa


   IS WILD-TYPE RAS AN ANTAGONIST OF ONCOGENIC RAS?
TOP
 ABSTRACT
 INTRODUCTION
 DIVERSE ROLES OF WILD-TYPE...
 GROWTH-SUPPRESSIVE NATURE OF...
 IS WILD-TYPE RAS AN...
ROLE OF WILD-TYPE RAS-GDP
 ROLE OF WILD-TYPE RAS-GTP
 WILD-TYPE VS. ONCOGENIC RAS
 CONCLUSIONS
 REFERENCES
 
Nature has devised an amazing method to regulate the activity of the native enzymes by creating the inactive-enzyme homologues (62) . Even in the Ras superfamily, the substitution of catalytic glutamine in the Ras homologue, Rap 1 renders it inactive for GTP hydrolysis (63) . This substitution makes Rap-1 act as an antagonist of Ras. Mutations existing in the oncogenic ras result in very low GTPase activity compared with the wild-type form. The striking difference in GTPase activity between the two forms of Ras is used as an analogy to the active-inactive enzyme homologues to speculate that wild-type Ras can antagonize the oncogenic form. In view of the fact that oncogenic Ras is considered dominant over the wild-type, the parallelism drawn between the inactive-active enzyme homologues and wild vs. oncogenic Ras will raise the issue of which of the two forms of Ras is dominant.

In tumors where only one of the ras allele is mutated, one would expect a similar level of expression of mutant and wild-type Ras but, at least in the mouse lung tumors overexpression of oncogenic Ras has been observed (48 , 64 , 65) . Even if there is an equal level of expression of the two forms of Ras, the oncogenic Ras is likely to be dominant over wild-type. This is because only a negligible fraction of wild-type Ras exists in the active GTP-bound state compared with the oncogenic Ras (see Table 1 ). Most Ras targets initiate signaling by interacting with the GTP-bound form, hence the possibility of coexisting wild-type ras allele to act in a dominant manner is remote. The dominant nature of oncogenic ras, however, is questioned based on the following observations: 1) single copy of constitutively active oncogenic H-ras allele is unable to transform the Rat-1 cells (66) , 2) transformation by oncogenic ras is suppressed by overexpressing wild-type ras (40 41 42 43) , and 3) moderate expression of oncogenic ras, when under the control of weak promoters, is unable to induce transformed morphology (67) . Recent findings that physiological level of oncogenic Ras is sufficient to immortalize the cells, however, reassert a dominant nature of oncogenic Ras over the wild-type (58 59 60) . It must be noted that in the transgenic animals (K-raswild-type/oncogenic), where the oncogenic Ras is under control of endogenous promoter, only certain cell/tissue types show tumor formation. Does this mean that wild-type Ras exerts a oncosuppressive function in other tissue types that do not show malignant features?

In spite of these differing reports, the mechanism by which wild-type Ras can cause growth suppression is unclear. It has been speculated that wild-type Ras can bring about growth suppression by contesting for the same targets as oncogenic Ras or by interacting with an unexplored downstream target (1 , 2 , 43) . We have tried to elaborate on these possibilities and hypothesize that wild-type Ras can oppose the functioning of oncogenic form. A proposal is given below for the role for wild-type Ras in GDP/GTP-bound state by which it can abrogate or antagonize the function of the coexisting oncogenic counterpart.


   ROLE OF WILD-TYPE RAS-GDP
TOP
 ABSTRACT
 INTRODUCTION
 DIVERSE ROLES OF WILD-TYPE...
 GROWTH-SUPPRESSIVE NATURE OF...
 IS WILD-TYPE RAS AN...
 ROLE OF WILD-TYPE RAS-GDP
ROLE OF WILD-TYPE RAS-GTP
 WILD-TYPE VS. ONCOGENIC RAS
 CONCLUSIONS
 REFERENCES
 
Wild-type Ras-GDP appears to act as a negative regulator of oncogenic Ras. This is based on observations that overexpression of wild-type Ras existing predominantly in a GDP state can suppress the transformation induced by the oncogenic form (40 41 42 43) . It was proposed earlier that Ras-GDP can act in a codominant fashion to Ras-GTP (1 , 2 , 68) . This leads to the question of whether Ras-GDP can have a role in signaling. Signaling exclusive to Ras-GDP still is not clear. An interesting finding describes binding of the transcriptional factor, Aiolos, only to the wild-type Ras-GDP and not to the GTP-bound form (69) . In IL-2-deprived T cells, the Ras-Aiolos interaction sequesters Aiolos to the cytoplasm and prevents its translocation to the nucleus, indicating a novel signaling pathway of the Ras-GDP complex.

Supportive evidence on functioning of the GDP-bound Ras form is made by making an analogy between the wild-type and mutant N17Ras, both of which exist in a GDP-bound state. The fact that N17Ras can effectively block the transformation by the oncogenic Ras is supportive of a signaling role for GDP-bound form of proteins (22 , 68) . Besides blocking endogenous Ras functions, the N17Ras mutant can initiate independent signaling mechanisms. It has been shown that inhibition of transcriptional factor Elk-1 is exclusive to the N17Ras and not exhibited by L61S186Ras, a GTP-bound interfering Ras mutant, demonstrating signaling events mutually exclusive to GDP- and GTP-bound states (68) . The growth suppression mediated by N17Ras is by Elk-1 inhibition and is independent of MAPK activity; wild-type Ras brings about oncosuppression by inhibiting the MAPK activity (42) . It therefore must be addressed whether the growth inhibition by wild-type Ras when mediated in its GDP-bound form occurs by antagonizing, directly or indirectly, pathways up-regulated by the constitutively active oncogenic Ras.

It was suggested earlier that the growth-suppressive activity of wild-type Ras might be initiated by its specific binding to tumor suppressors like RASSF1 and its homologue Nore, but this has now been ruled out, at least in Cos-7 cells (1 , 70) . For many small GTPases, the accepted dogma is that the GDP-bound form of protein is inactive whereas the GTP-bound form is the active state, which brings about the specific signaling. However, there are reports for small GTPases such as like Ran (71) , Bud1 (72) Rac (73 , 74) , Rho (75) , and Rab27 (76) interacting with downstream targets in the GDP-bound form. In light of these observations, one has to reevaluate the existing paradigm that GDP-bound Ras is inactive and not involved in active signaling events. It is possible that Ras-GDP can counteract the action of oncogenic Ras by sequestering the downstream targets of oncogenic Ras into an inactive state or by interacting with a distinct class of targets (Fig. 2 ).



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  		Figure 2. Schematic representation of a proposed model on the inhibitory effect of GTP/GDP-bound wild-type (WT) Ras. A) WT-Ras-GDP can counteract the effects of oncogenic Ras by titrating out protein target A, needed for transformation or by interacting with target B, it can initiate a signaling event opposing the action of oncogenic Ras. B) WT-Ras-GTP by binding to same (X) or different target (Y) can negate the action of oncogenic Ras, which in turn can be overcome by the oncogenic form in the presence of coordinating events such as loss of tumors suppressors. When bound to the same target X, the wild-type Ras can sequester it into a latent signaling complex or initiate a unique signaling pathway through target Q, leading to growth arrest.


   ROLE OF WILD-TYPE RAS-GTP
TOP
 ABSTRACT
 INTRODUCTION
 DIVERSE ROLES OF WILD-TYPE...
 GROWTH-SUPPRESSIVE NATURE OF...
 IS WILD-TYPE RAS AN...
 ROLE OF WILD-TYPE RAS-GDP
 ROLE OF WILD-TYPE RAS-GTP
WILD-TYPE VS. ONCOGENIC RAS
 CONCLUSIONS
 REFERENCES
 
The role of activated wild-type Ras in cell cycle execution and proliferation is well understood. Can the activated Ras in GTP-bound state antagonize the constitutively active oncogenic Ras and bring about oncosuppression? It is already known that activated wild-type Ras and its oncogenic form can both bind similar targets such as Raf, Nore, and RASSF1. Thus, it is likely that wild-type Ras-GTP can compete for similar downstream targets and titrate them out (Fig. 2) . In the mouse fibroblasts, a pool of GTP-bound cellular N-Ras exists in a latent signaling complex with c-Raf-1 and PKC {zeta} (77) . Thus, by sequestering out the targets into inefficient signaling complex, Ras-GTP can impede the signaling response of the oncogenic form. This argument appears weak in view of the fact that the amount of wild-type Ras-GTP is negligible compared with the coexisting oncogenic Ras-GTP. However, it is possible that wild-type Ras, when overexpressed compared with the oncogenic form, can tip the balance in favor of growth inhibition.

A stronger possibility is that wild-type Ras-GTP can oppose the functioning of mutant Ras by activating a distinct signaling response. This poses the question, Can activated wild-type Ras initiate a unique signaling event? Two major lines of evidence indicate that the signaling mediated by activated wild-type Ras is different from its oncogenic counterpart. The first comes from molecular dynamic studies that show differences in the structures of the wild-type Ras and mutant V12Ras when bound to GTPase-activating protein (78) . The differences in molecular structures are indicative of different modes of action for the two forms of Ras. The structural difference between the wild-type and oncogenic Ras has been effectively used to design synthetic peptides, which can selectively target the oncogenic Ras protein (79) . The second line of evidence emanates from studies that point to a preferential interaction of wild-type and oncogenic Ras with different signaling partners (Table 4 ). Inhibitors of arginine methyltransferases have been shown to block the oncogenic but not the activated wild-type, Ras-mediated oocyte maturation, thus indicating a signaling mechanism unique to two forms of Ras (84) . These studies indicate that besides having overlapping signaling pathways, oncogenic and wild-type Ras can utilize discrete signaling events.


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  		Table 4. Differences in signaling events mediated by oncogenic and wild-type rasa

It is well known that changing the intensity or duration of Ras signaling can have different cellular outcomes (85 , 86) . By using peptides specific to oncogenic and wild-type Ras, it has been shown that oncogenic Ras causes a sustained activation of both MAPK and JNK in oocytes whereas wild-type Ras activated by insulin causes only a low level of MAPK/JNK activation (87) . It remains to be seen whether changing the signaling intensity of the wild-type Ras can bring about diverse cellular outcomes. A major challenge lies ahead in unraveling signaling events exclusive to wild-type Ras isoforms that can interfere with oncogenic signaling events.


   WILD-TYPE VS. ONCOGENIC RAS
TOP
 ABSTRACT
 INTRODUCTION
 DIVERSE ROLES OF WILD-TYPE...
 GROWTH-SUPPRESSIVE NATURE OF...
 IS WILD-TYPE RAS AN...
 ROLE OF WILD-TYPE RAS-GDP
 ROLE OF WILD-TYPE RAS-GTP
 WILD-TYPE VS. ONCOGENIC RAS
CONCLUSIONS
 REFERENCES
 
The opposing effects of wild-type and oncogenic ras elaborated above raise some questions. First, how can the wild-type or oncogenic ras overcome the influence of their coexisting counterparts? An important decisive factor is the cellular level of expression of wild-type vs. oncogenic protein. It has been seen that oncogenic Ras protein is overexpressed compared with wild-type Ras in tumors and transformed cell lines (48 , 64 , 65) . It must be addressed whether the overexpression of oncogenic Ras is because of more copy number, higher rate of transcription, or increased stability of the oncogenic protein. It has been shown that wild-type Ras induced its oncosuppressive activity only when its expression supercedes that of the oncogenic protein, thereby indicating that the expression level is an important decisive factor in the cellular outcome mediated by Ras (41) .

Second, how can amplification or hyperactivation of cellular ras in the absence of mutation lead to uncontrolled proliferation? Events such as loss or mutations in tumor suppressor(s) or amplification of oncogene(s) such as myc can cause autocrine growth factor secretions, and thereby convert the existing wild-type Ras-GDP to constitutively active Ras-GTP or stimulate the conversion of the latent Ras-GTP into an active signaling complex. This in turn can lead to a corresponding change in the signal intensity and duration leading to cellular transformation. Thus the cellular fate will depend on a fine balance existing between the wild-type ras and its oncogenic counterpart coupled to the genetic/epigenetic background of the cell (Fig. 3 ).



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  		Figure 3. The cellular fate of a cell containing oncogenic and wild-type Ras (WT-Ras) will depend on the balance existing between the two forms of Ras together with corresponding events such as loss of tumor suppressors, e.g., p53/Rb/NF1/p16INK/p19ARF or induction of cell cycle inhibitors such as cyclin-dependent kinase inhibitors (CDKIs).

It was shown lately that endogenous expression of oncogenic ras in K-raswild-type/oncogenic transgenic mice led to an early induction of tumors (58 59 60) . The physiological level of oncogenic K-Ras expression causes partial transformation of cells in vitro and development of lesions only in certain tissues in mice. These findings lead to the argument that dominance of wild/oncogenic Ras forms cannot be based solely on their relative level of protein expression and reiterate the importance of cellular context in determining the tumor protective/promoting effect of the wild-type Ras. However, in another transgenic animal model, it has been noted that induction of oncogenic K-ras under the control of a regulatable promoter leads to down-regulation of the endogenous wild-type Ras in the tumors (64) . It would be interesting to see whether in the recently developed K-raswild-type/oncogenic transgenic models the tumors show a similar decline in the expression of the wild-type Ras compared with the oncogenic form. Further, it needs to be determined whether the level of expression in the wild and oncogenic Ras is different in malignant and nonmalignant tissues. At least in the transgenic mice developing pancreatic cancer, the level of total Ras protein is higher than that of control animals, consistent with the expression of the oncogenic allele (58) . It therefore is likely that the expression level of Ras (wild vs. oncogenic) and the cellular context both influence the growth parameters of a cell.

If it is possible to knock down the wild-type allele in the recently developed K-raswild-type/oncogenic genetic background, will the tumors be more widespread and aggressive? If in the conditionally activated homozygous K-rasoncogenic/oncogenic genetic background the wild-type allele is reintroduced, will it be sufficient to revert the transformed phenotype? Clearly there are more questions than answers as to the role of wild-type Ras, and sophisticated manipulations of both in vivo and in vitro models can take us one step closer to defining the role of this multifaceted protein.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 DIVERSE ROLES OF WILD-TYPE...
 GROWTH-SUPPRESSIVE NATURE OF...
 IS WILD-TYPE RAS AN...
 ROLE OF WILD-TYPE RAS-GDP
 ROLE OF WILD-TYPE RAS-GTP
 WILD-TYPE VS. ONCOGENIC RAS
 CONCLUSIONS
REFERENCES
 
Although the existing literature elaborates the functioning of the oncogenic Ras, the exact role of wild-type Ras remains unresolved. The foregoing therefore tries to evaluate the less well understood function of wild-type Ras in relation to its growth-suppressive activity. Future challenges in Ras biology will require not only evaluating the role of the wild-type Ras and its signaling pathways, but understanding how it differs from its oncogenic counterpart. This will help in designing better targets for oncogenic Ras without disrupting the functioning of the normal counterpart; as well, the growth-suppressive nature of wild-type Ras itself can be exploited as a candidate for cancer therapy. In conclusion, until the mechanism of action of wild-type ras is fully understood, Ras biology will remain an enigma.


   ACKNOWLEDGMENTS
 
We thank Nirotpal Mrinal, T. Ramasarma, and Lucy M. Anderson for critical reading of the manuscript. A.S. is supported by fellowship from C.S.I.R. A grant from Fogarty International, NIH (grant no: RO1 TW006195-02) to G.R. is acknowledged. We apologize to all those authors whose work could not be cited because of space constraint.

Received for publication June 29, 2004. Accepted for publication October 6, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 DIVERSE ROLES OF WILD-TYPE...
 GROWTH-SUPPRESSIVE NATURE OF...
 IS WILD-TYPE RAS AN...
 ROLE OF WILD-TYPE RAS-GDP
 ROLE OF WILD-TYPE RAS-GTP
 WILD-TYPE VS. ONCOGENIC RAS
 CONCLUSIONS
 REFERENCES
 

  1. Pfeifer, G. P. (2001) A new verdict for an old convict. Nat. Genet. 29,3-4[CrossRef][Medline]
  2. Spandidos, D. A., Sourvinos, G., Tsatsanis, C., Zafiropoulos, A. (2002) Normal ras genes: their onco-suppressor and pro-apoptotic functions. Int. J. Oncol. 21,237-241[Medline]
  3. Shields, J. M., Pruitt, K., McFall, A., Shaub, A., Der, C. J. (2000) Understanding Ras: ‘it ain’t over ’til it’s over’. Trends Cell Biol. 10,147-154[CrossRef][Medline]
  4. Hamad, N. M., Elconin, J. H., Karnoub, A. E., Bai, W., Rich, J. N., Abraham, R. T., Der, C. J., Counter, C. M. (2002) Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev. 16,2045-2057[Abstract/Free Full Text]
  5. Li, G., Zhang, X. C. (2004) GTP hydrolysis mechanism of Ras-like GTPases. J. Mol. Biol. 340,921-932[CrossRef][Medline]
  6. Scheele, J. S., Rhee, J. M., Boss, G. R. (1995) Determination of absolute amounts of GDP and GTP-bound to Ras in mammalian cells: comparison of parental and Ras-overproducing NIH 3T3 fibroblasts. Proc. Natl. Acad. Sci. USA 92,1097-1100[Abstract/Free Full Text]
  7. Plowman, S. J., Williamson, D. J., O’Sullivan, M. J., Doig, J., Ritchie, A. M., Harrison, D. J., Melton, D. W., Arends, M. J., Hooper, M. L., Patek, C. E. (2003) While K-ras is essential for mouse development, expression of the K-ras 4A splice variant is dispensable. Mol. Cell. Biol. 23,9245-9250[Abstract/Free Full Text]
  8. Esteban, L. M., Vicario-Abejon, C., Fernandez-Salguero, P., Fernandez-Medarde, A., Swaminathan, N., Yienger, K., Lopez, E., Malumbres, M., McKay, R., Ward, J. M., et al (2001) Targeted genomic disruption of H-ras and N-ras, individually or in combination, reveals the dispensability of both loci for mouse growth and development. Mol. Cell. Biol. 21,1444-1452[Abstract/Free Full Text]
  9. de Castro, I. P., Diaz, R., Malumbres, M., Hernandez, M. I., Jagirdar, J., Jimenez, M., Ahn, D., Pellicer, A. (2003) Mice deficient for N-ras: impaired antiviral immune response and T-cell function. Cancer Res. 63,1615-1622[Abstract/Free Full Text]
  10. Wolfman, J. C., Wolfman, A. (2000) Endogenous c-N-Ras provides a steady-state anti-apoptotic signal. J. Biol. Chem. 275,19315-19323[Abstract/Free Full Text]
  11. Wolfman, J. C., Palmby, T., Der, C. J., Wolfman, A. (2002) Cellular N-Ras promotes cell survival by downregulation of Jun N-terminal protein kinase and p38. Mol. Cell. Biol. 22,1589-1606[Abstract/Free Full Text]
  12. Liao, J., Wolfman, J. C., Wolfman, A. (2003) K-ras regulates the steady-state expression of matrix metalloproteinase 2 in fibroblasts. J. Biol. Chem. 278,31871-31878[Abstract/Free Full Text]
  13. Matsui, T., Kinoshita, T., Morikawa, Y., Tohya, K., Katsuki, M., Ito, Y., Kamiya, A., Miyajima, A. (2002) K-Ras mediates cytokine-induced formation of E-cadherin-based adherens junctions during liver development. EMBO J. 21,1021-1030[CrossRef][Medline]
  14. Kremer, N. E., D’Arcangelo, G., Thomas, S. M., DeMarco, M., Brugge, J. S., Halegoua, S. (1991) Signal transduction by nerve growth factor and fibroblast growth factor in PC12 cells requires a sequence of src and ras actions. J. Cell Biol. 115,809-819[Abstract/Free Full Text]
  15. Baltus, E., Hanocq-Quertier, J., Hanocq, F., Brachet, J. (1998) Injection of an antibody against a p21 c-Ha-ras protein inhibits cleavage in axolotl eggs. Proc. Natl. Acad. Sci. USA 85,502-506[CrossRef]
  16. Mulcahy, L. S., Smith, M. R., Stacey, D. W. (1985) Requirement for ras proto-oncogene function during serum-stimulated growth of NIH 3T3 cells. Nature (London) 313,241-243[CrossRef][Medline]
  17. Dobrowolski, S., Harter, M., Stacey, D. W. (1994) Cellular ras activity is required for passage through multiple points of the G0/G1 phase in BALB/c 3T3 cells. Mol. Cell. Biol. 14,5441-5449[Abstract/Free Full Text]
  18. Howe, P. H., Dobrowolski, S. F., Reddy, K. B., Stacey, D. W. (1993) Release from G1 growth arrest by transforming growth factor beta 1 requires cellular ras activity. J. Biol. Chem. 268,21448-21452[Abstract/Free Full Text]
  19. Swan, K. A., Alberola-Ila, J., Gross, J. A., Appleby, M. W., Forbush, K. A., Thomas, J. F., Perlmutter, R. M. (1995) Involvement of p21ras distinguishes positive and negative selection in thymocytes. EMBO J. 14,276-285[Medline]
  20. Iritani, B. M., Forbush, K. A., Farrar, M. A., Perlmutter, R. M. (1997) Control of B cell development by Ras-mediated activation of Raf. EMBO J. 16,7019-7031[CrossRef][Medline]
  21. D’Arcangelo, G., Halegoua, S. (1993) A branched signaling pathway for nerve growth factor is revealed by Src-, Ras-, and Raf-mediated gene inductions. Mol. Cell. Biol. 13,3146-3155[Abstract/Free Full Text]
  22. Stacey, D. W., Feig, L. A., Gibbs, J. B. (1991) Dominant inhibitory Ras mutants selectively inhibit the activity of either cellular or oncogenic Ras. Mol. Cell. Biol. 11,4053-4064[Abstract/Free Full Text]
  23. Kaplan, J. B. (1994) Biological activity of human N-ras and K-ras genes containing the Asn17 dominant negative mutation. Oncol. Res. 6,611-615[Medline]
  24. Aktas, H., Cai, H., Cooper, G. M. (1997) Ras links growth factor signaling to the cell cycle machinery via regulation of cyclin D1 and the Cdk inhibitor p27KIP1. Mol. Cell. Biol. 17,3850-3857[Abstract]
  25. Chen, G., Oh, S., Monia, B. P., Stacey, D. W. (1996) Antisense oligonucleotides demonstrate a dominant role of c-Ki-RAS proteins in regulating the proliferation of diploid human fibroblasts. J. Biol. Chem. 271,28259-28265[Abstract/Free Full Text]
  26. Sharpe, C. C., Dockrell, M. E., Noor, M. I., Monia, B. P., Hendry, B. M. (2000) Role of Ras isoforms in the stimulated proliferation of human renal fibroblasts in primary culture. J. Am. Soc. Nephrol. 11,1600-1606[Abstract/Free Full Text]
  27. Sharpe, C. C., Dockrell, M. E., Scott, R., Noor, M. I., Cowsert, L. M., Monia, B. P., Hendry, B. M. (1999) Evidence of a role for Ki-Ras in the stimulated proliferation of renal fibroblasts. J. Am. Soc. Nephrol. 10,1186-1192[Abstract/Free Full Text]
  28. Taylor, S. J., Shalloway, D. (1996) Cell cycle-dependent activation of Ras. Curr. Biol. 6,1621-1627[CrossRef][Medline]
  29. Gille, H., Downward, J. (1999) Multiple ras effector pathways contribute to G(1) cell cycle progression. J. Biol. Chem. 274,22033-22040[Abstract/Free Full Text]
  30. Takuwa, N., Takuwa, Y. (1997) Ras activity late in G1 phase required for p27kip1 downregulation, passage through the restriction point, and entry into S phase in growth factor-stimulated NIH 3T3 fibroblasts. Mol. Cell. Biol. 17,5348-5358[Abstract]
  31. Sa, G., Hitomi, M., Harwalkar, J., Stacey, A. W., Chen, G., Stacey, D. W. (2002) Ras is active throughout the cell cycle, but is able to induce cyclin D1 only during G2 phase. Cell Cycle 1,50-58[Medline]
  32. Crespo, P., Leon, J. (2000) Ras proteins in the control of the cell cycle and cell differentiation. Cell. Mol. Life Sci. 57,1613-1636[CrossRef][Medline]
  33. Thrane, E. V., Becher, R., Lag, M., Refsnes, M., Huitfeldt, H. S., Schwarze, P. E. (1997) Differential distribution and increased levels of ras proteins during lung development. Exp. Lung Res. 23,35-49[Medline]
  34. Pells, S., Divjak, M., Romanowski, P., Impey, H., Hawkins, N. J., Clarke, A. R., Hooper, M. L., Williamson, D. J. (1997) Developmentally-regulated expression of murine K-ras isoforms. Oncogene 15,1781-1786[CrossRef][Medline]
  35. Sithanandam, G., Ramakrishna, G., Diwan, B. A., Anderson, L. M. (1998) Selective mutation of K-ras by N-ethylnitrosourea shifts from codon 12 to codon 61 during fetal mouse lung maturation. Oncogene 17,493-502[CrossRef][Medline]
  36. Ramakrishna, G., Sithanandam, G., Cheng, R. Y., Fornwald, L. W., Smith, G. T., Diwan, B. A., Anderson, L. M. (2000) K-ras p21 expression and activity in lung and lung tumors. Exp. Lung Res. 26,659-671[CrossRef][Medline]
  37. Kammouni, W., Ramakrishna, G., Sithanandam, G., Smith, G. T., Fornwald, L. W., Masuda, A., Takahashi, T., Anderson, L. M. (2002) Increased K-ras protein and activity in mouse and human lung epithelial cells at confluence. Cell. Growth. Differ. 13,441-448[Abstract/Free Full Text]
  38. Chaturvedi, V., Cesnjaj, M., Bacon, P., Panella, J., Choubey, D., Diaz, M. O., Nickoloff, B. J. (2003) Role of INK4a/Arf locus-encoded senescent checkpoints activated in normal and psoriatic keratinocytes. Am. J. Pathol. 162,161-170[Abstract/Free Full Text]
  39. Feig, L. A. (1999) Tools of the trade: use of dominant-inhibitory mutants of Ras-family GTPases. Nat. Cell Biol. 1,E25-E27[CrossRef][Medline]
  40. Spandidos, A., Wilkie, N. M. (1988) The normal human H-ras1 gene can act as an onco-suppressor. Br. J. Cancer Suppl. 9,67-71[Medline]
  41. Spandidos, D. A., Frame, M., Wilkie, N. M. (1990) Expression of the normal H-ras1 gene can suppress the transformed and tumorigenic phenotypes induced by mutant ras genes. Anticancer Res. 10,1543-1554[Medline]
  42. Zhang, Z., Wang, Y., Vikis, H. G., Johnson, L., Liu, G., Li, J., Anderson, M. W., Sills, R. C., Hong, H. L., Devereux, T. R., et al (2001) Wildtype Kras2 can inhibit lung carcinogenesis in mice. Nat. Genet. 29,25-33[CrossRef][Medline]
  43. Diaz, R., Ahn, D., Lopez-Barcons, L., Malumbres, M., Perez de Castro, I., Lue, J., Ferrer-Miralles, N., Mangues, R., Tsong, J., Garcia, R., et al (2002) The N-ras proto-oncogene can suppress the malignant phenotype in the presence or absence of its oncogene. Cancer Res. 62,4514-4518[Abstract/Free Full Text]
  44. Delgado, M. D., Vaque, J. P., Arozarena, I., Lopez-Ilasaca, M. A., Martinez, C., Crespo, P., Leon, J. (2000) H-, K- and N-Ras inhibit myeloid leukemia cell proliferation by a p21WAF1-dependent mechanism. Oncogene 19,783-790[CrossRef][Medline]
  45. James, R. M., Arends, M. J., Plowman, S. J., Brooks, D. G., Miles, C. G., West, J. D., Patek, C. E. (2003) K-ras proto-oncogene exhibits tumor suppressor activity as its absence promotes tumorigenesis in murine teratomas. Mol. Cancer Res. 11,820-825
  46. Guerrero, I., Villasante, A., Corces, V., Pellicer, A. (1985) Loss of the normal N-ras allele in a mouse thymic lymphoma induced by a chemical carcinogen. Proc. Natl. Acad. Sci. USA 82,7810-7814[Abstract/Free Full Text]
  47. Bremner, R., Balmain, A. (1990) Genetic changes in skin tumor progression: correlation between presence of a mutant ras gene and loss of heterozygosity on mouse chromosome 7. Cell 61,407-417[CrossRef][Medline]
  48. Johnson, L., Mercer, K., Greenbaum, D., Bronson, R. T., Crowley, D., Tuveson, D. A., Jacks, T. (2001) Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature (London) 410,1111-1116[CrossRef][Medline]
  49. Takeuchi, S., Mori, N., Koike, M., Slater, J., Park, S., Miller, C. W., Miyoshi, I., Koeffler, H. P. (1996) Frequent loss of heterozygosity in region of the KIP1 locus in non-small cell lung cancer: evidence for a new tumor suppressor gene on the short arm of chromosome 12. Cancer Res. 56,38-740
  50. Sanchez-Cespedes, M., Ahrendt, S. A., Piantadosi, S., Rosell, R., Monzo, M., Wu, L., Westra, W. H., Yang, S. C., Jen, J., Sidransky, D. (2001) Chromosomal alterations in lung adenocarcinoma from smokers and nonsmokers. Cancer Res. 61,1309-1313[Abstract/Free Full Text]
  51. Kibel, A. S., Schutte, M., Kern, S. E., Isaacs, W. B., Bova, G. S. (1998) Identification of 12p as a region of frequent deletion in advanced prostate cancer. Cancer Res. 58,5652-5655[Abstract/Free Full Text]
  52. Mahlamaki, E. H., Hoglund, M., Gorunova, L., Karhu, R., Dawiskiba, S., Andren-Sandberg, A., Kallioniemi, O. P., Johansson, B. (1997) Comparative genomic hybridization reveals frequent gains of 20q, 8q, 11q, 12p, and 17q, and losses of 18q, 9p, and 15q in pancreatic cancer. Genes Chromosomes Cancer 20,383-391[CrossRef][Medline]
  53. Sourvinos, G., Kiaris, H., Tsikkinis, A., Vassilaros, S., Spandidos, D. A. (1997) Microsatellite instability and loss of heterozygosity in primary breast tumours. Tumour Biol. 18,157-166[Medline]
  54. Baccichet, A., Sinnett, D. (1997) Frequent deletion of chromosome 12p12.3 in children with acute lymphoblastic leukaemia. Br. J. Haematol. 99,107-114[CrossRef][Medline]
  55. Tsunematsu, S., Saito, H., Kagawa, T., Morizane, T., Hata, J., Nakamura, T., Ishii, H., Tsuchiya, M., Nomura, T., Katsuki, M. (1994) Hepatic tumors induced by carbon tetrachloride in transgenic mice carrying a human c-H-ras proto-oncogene without mutations. Int. J. Cancer 59,554-559[Medline]
  56. Maruyama, C., Tomisawa, M., Wakana, S., Yamazaki, H., Kijima, H., Suemizu, H., Ohnishi, Y., Urano, K., Hioki, K., Usui, T., et al (2001) Overexpression of human H-ras transgene is responsible for tumors induced by chemical carcinogens in mice. Oncol. Rep. 8,233-237[Medline]
  57. Ise, K., Nakamura, K., Nakao, K., Shimizu, S., Harada, H., Ichise, T., Miyoshi, J., Gondo, Y., Ishikawa, T., Aiba, A., et al (2000) Targeted deletion of the H-ras gene decreases tumor formation in mouse skin carcinogenesis. Oncogene 19,2951-2956[CrossRef][Medline]
  58. Tuveson, D. A., Shaw, A. T., Willis, N. A., Silver, D. P., Jackson, E. L., Chang, S., Mercer, K. L., Grochow, R., Hock, H., Crowley, D., et al (2004) Endogenous oncogenic K-ras (G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 4,375-387
  59. Hingorani, S. R., Petricoin, E. F., Maitra, A., Rajapakse, V., King, C., Jacobetz, M. A., Ross, S., Conrads, T. P., Veenstra, T. D., Hitt, B. A., et al (2003) Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4,437-450[CrossRef][Medline]
  60. Guerra, C., Mijimolle, N., Dhawahir, A., Dubus, P., Barradas, M., Serrano, M., Campuzano, V., Barbacid, M. (2003) Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell 4,111-120[CrossRef][Medline]
  61. Diaz, R, Lopez-Barcons, L., Ahn, D., Garcia-Espana, A., Yoon, A., Matthews, J., Mangues, R., Perez-Soler, R., Pellicer, A. (2004) Complex effects of Ras proto-oncogenes in tumorigenesis. Carcinogenesis 25,535-539[Abstract/Free Full Text]
  62. Pils, B., Schultz, J. (2004) Inactive enzyme-homologues find new function in regulatory processes. J. Mol. Biol. 340,399-404[CrossRef][Medline]
  63. Kitayama, H., Sugimoto, Y., Matsuzaki, T., Ikawa, Y., Noda, M. (1989) A ras-related gene with transformation suppressor activity. Cell 56,77-84[CrossRef][Medline]
  64. Fisher, G. H., Wellen, S. L., Klimstra, D., Lenczowski, J. M., Tichelaar, J. W., Lizak, M. J., Whitsett, J. A., Koretsky, A., Varmus, H. E. (2001) Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev. 15,3249-3262[Abstract/Free Full Text]
  65. Uchiyama, M., Usami, N., Kondo, M., Mori, S., Ito, M., Ito, G., Yoshioka, H., Imaizumi, M., Ueda, Y., Takahashi, M., et al (2003) Loss of heterozygosity of chromosome 12p does not correlate with KRAS mutation in non-small cell lung cancer. Int. J. Cancer 107,962-969[CrossRef][Medline]
  66. Finney, R. E., Bishop, J. M. (1993) Predisposition to neoplastic transformation caused by gene replacement of H-ras1. Science 260,1524-1527[Abstract/Free Full Text]
  67. Cichutek, K., Duesberg, P. H. (1989) Recombinant BALB and Harvey sarcoma viruses with normal proto-ras-coding regions transform embryo cells in culture and cause tumors in mice. J. Virol. 63,1377-1383[Abstract/Free Full Text]
  68. Stewart, S., Guan, K. L. (2000) The dominant negative Ras mutant, N17Ras, can inhibit signaling independently of blocking Ras activation. J. Biol. Chem. 275,8854-8862[Abstract/Free Full Text]
  69. Romero, F., Martinez-A, C., Camonis, J., Rebollo, A. (1999) Aiolos transcription factor controls cell death in T cells by regulating Bcl-2 expression and its cellular localization. EMBO J. 18,3419-3430[CrossRef][Medline]
  70. Ortiz-Vega, S., Khokhlatchev, A., Nedwidek, M., Zhang, X. F., Dammann, R., Pfeifer, G. P., Avruch, J. (2002) The putative tumor suppressor RASSF1A homodimerizes and heterodimerizes with the Ras-GTP binding protein Nore1. Oncogene 21,1381-1390[CrossRef][Medline]
  71. Nehrbass, U., Blobel, G. (1996) Role of the nuclear transport factor p10 in nuclear import. Science 272,120-122[Abstract]
  72. Park, H. O., Bi, E., Pringle, J. R., Herskowitz, I. (1997) Two active states of the Ras-related Bud1/Rsr1 protein bind to different effectors to determine yeast cell polarity. Proc. Natl. Acad. Sci. USA 94,4463-4468[Abstract/Free Full Text]
  73. Tarricone, C., Xiao, B., Justin, N., Walker, P. A., Rittinger, K., Gamblin, S. J., Smerdon, S. J. (2001) The structural basis of Arfaptin-mediated cross-talk between Rac and Arf signalling pathways. Nature (London) 411,215-219[CrossRef][Medline]
  74. Sigal, N., Gorzalczany, Y., Sarfstein, R., Weinbaum, C., Zheng, Y., Pick, E. (2002) The guanine nucleotide exchange factor trio activates the phagocyte NADPH oxidase in the absence of GDP to GTP exchange on Rac. "The emperor’s new clothes". J. Biol. Chem. 278,4854-4861
  75. Tian, D., Litvak, V., Toledo-Rodriguez, M., Carmon, S., Lev, S. (2002) Nir2, a novel regulator of cell morphogenesis. Mol. Cell. Biol. 22,2650-2662[Abstract/Free Full Text]
  76. Fukuda, M. (2003) Slp4-a/granuphilin-a inhibits dense-core vesicle exocytosis through interaction with the GDP-bound form of Rab27A in PC12 cells. J. Biol. Chem. 278,15390-15396[Abstract/Free Full Text]
  77. Hamilton, M., Liao, J., Cathcart, M. K., Wolfman, A. (2001) Constitutive association of c-N-Ras with c-Raf-1 and protein kinase C epsilon in latent signaling modules. J. Biol. Chem. 276,29079-29090[Abstract/Free Full Text]
  78. Chen, J. M., Friedman, F. K., Brandt-Rauf, P. W., Pincus, M. R., Chie, L. (2002) Comparison of the average structures, from molecular dynamics, of complexes of GTPase-activating protein (GAP) with oncogenic and wild-type ras-p21: identification of potential effector domains. J. Protein Chem. 21,349-359[CrossRef][Medline]
  79. Kanovsky, M., Michl, J., Botzolaki, G., Morin, J., Kovac, C., Chung, D. L., Chie, L., Friedman, F. K., Pincus, M. R. (2003) Peptides designed from molecular modeling studies of the ras-p21 protein induce phenotypic reversion of a pancreatic carcinoma cell line but have no effect on normal pancreatic acinar cell growth. Cancer Chemother. Pharmacol. 52,202-208[CrossRef][Medline]
  80. Adler, V., Pincus, M. R., Brandt-Rauf, P. W., Ronai, Z. (1995) Complexes of p21RAS with JUN N-terminal kinase and JUN proteins. Proc. Natl. Acad. Sci. USA 92,10585-10589[Abstract/Free Full Text]
  81. Vos, M. D., Ellis, C. A., Elam, C., Ulku, A. S., Taylor, B. J., Clark, G. J. (2003) RASSF2 is a novel K-Ras-specific effector and potential tumor suppressor. J. Biol. Chem. 278,28045-28051[Abstract/Free Full Text]
  82. Chie, L., Qu, Y., Chung, D., Boutjdir, M., Pincus, M. R. (2003) Oncogenic and activated wild-type ras-p21 proteins induce different isoforms of protein kinase C in mitogenic signal transduction. J. Protein Chem. 22,625-629[CrossRef][Medline]
  83. Lucas, L., Penalva, V., Ramirez de Molina, A., Del Peso, L., Lacal, J. (2000) Modulation of phospholipase D by Ras proteins mediated by its effectors Ral-GDS, PI3K and Raf-1. Int. J. Oncol. 21,477-485
  84. Chie, L., Cook, J. R., Chung, D., Hoffmann, R., Yang, Z., Kim, Y., Pestka, S., Pincus, M. R. (2003) A protein methyl transferase, PRMT5, selectively blocks oncogenic ras-p21 mitogenic signal transduction. Ann. Clin. Lab. Sci. 33,200-207[Abstract/Free Full Text]
  85. Marshall, C. J. (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80,179-185[CrossRef][Medline]
  86. Deng, Q., Liao, R., Wu, B. L., Sun, P. (2004) High intensity ras signaling induces premature senescence by activating p38 pathway in primary human fibroblasts. J. Biol. Chem. 279,1050-1059[Abstract/Free Full Text]
  87. Ranginwale, M., Smith, S., Flom, J., Chie, L., Kanovsky, M., Chung, D., Friedman, F. K., Robinson, R. C., Brandt-Rauf, P. W., Yamaizumi, Z., et al (2001) Differences in patterns of activation of MAP kinases induced by oncogenic ras-p21 and insulin in oocytes. Exp. Cell Res. 269,162-169[CrossRef][Medline]



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