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Published as doi: 10.1096/fj.07-8900rev.
 (The FASEB Journal. 2007;21:3786-3794.)
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The role of pre-replicative complex (pre-RC) components in oncogenesis

Eric Lau*,{dagger}, Toshiya Tsuji*, Liping Guo{ddagger}, Shih-Hsin Lu{ddagger} and Wei Jiang*,{ddagger},1

* The Burnham Institute for Medical Research, La Jolla, California, USA;

{dagger} Graduate Program in Molecular Pathology, University of California at San Diego, La Jolla, California, USA;

{ddagger} Cancer Institute, Chinese Academy of Medical Sciences, Beijing, China

1Correspondence: The Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. E-mail: wjiang{at}burnham.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PRE-RC PROTEINS AND RESTRICTION...
 PRE-RC PROTEINS AND TUMORS
 PRE-RC PROTEINS AND ONCOGENIC...
 CONCLUDING REMARKS
 REFERENCES
 
Normal DNA replication is stringently regulated to ensure a timely occurrence no more than once per cell cycle. Abrogation of the exquisite control mechanisms that maintain this process results in detrimental gains and losses of genomic DNA commonly seen in cancer and developmental defects. Replication initiation proteins, known as prereplicative complex (pre-RC) proteins, serve as a primary level of regulation, controlling when DNA replication can begin. Unsurprisingly, several pre-RC proteins are overexpressed in cancer and serve as good tumor markers. However, their direct correlation with increasing tumor grade and poor prognosis has posed a long-standing question: Are pre-RC proteins oncogenic? Recently, a growing body of data indicates that deregulation of individual pre-RC proteins, either by overexpression or functional deficiency in several organismal models, results in significant and consistently perturbed cell cycle regulation, genomic instability, and, potentially, tumorigenesis. In this review, we examine this broad range of evidence suggesting that pre-RC proteins play roles during oncogenesis that are more than simply indicative of proliferation, supporting the notion that pre-RC proteins may potentially have significant diagnostic and therapeutic value.—Lau, E., Tsuji, T., Guo, L., Lu, S-H., Jiang, W. The role of pre-replicative complex (pre-RC) components in oncogenesis.


Key Words: DNA replication • pre-RC formation • tumorigenesis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PRE-RC PROTEINS AND RESTRICTION...
 PRE-RC PROTEINS AND TUMORS
 PRE-RC PROTEINS AND ONCOGENIC...
 CONCLUDING REMARKS
 REFERENCES
 
PROPER PASSAGE THROUGH THE CELL CYCLE ensures for complete transfer of the genome and viability from parental cells to subsequent daughter cells. While the majority of somatic cells are not actively cycling and rest in a G0 state, populations of actively cycling cells do reside in niches throughout the body, playing key roles in repopulating our tissues and maintaining immune function. Thus, perturbations in the cell cycle can spark fundamentally detrimental events, e.g., genomic instability or cell death, ultimately resulting in downstream pathological manifestations. S-phase DNA replication is a major cell cycle event that results in the impartment of a full and exact genome copy from parent to daughter cells. Hence, any mistakes and errors therein can potentially be deleterious, promoting genomic anomalies that lead to developmental defects and disease (for comprehensive reviews, see ref. 1 ).

Eukaryotes have evolved a multifaceted replication process that incorporates many levels of regulation and safeguards for replication initiation, repair, and checkpoints, all of which guarantee replication precision and replication limited to once and once only per cell cycle. Restriction of a single round of DNA replication is essential for prevention of the erroneous genomic aneuploidy that is common in most cancers (1 2 3) . Defects in DNA replication have been demonstrated to result from the direct inhibition or abrogation of repair and checkpoint mechanisms. To present, there has been little evidence, if any, demonstrating inherent oncogenicity of DNA replication initiation machinery. In this review, we examine evidence and recent studies of replication initiation proteins that indicate their direct involvement in oncogenesis.


   PRE-RC PROTEINS AND RESTRICTION OF DNA REPLICATION TO ONCE PER CELL CYCLE
TOP
 ABSTRACT
 INTRODUCTION
 PRE-RC PROTEINS AND RESTRICTION...
PRE-RC PROTEINS AND TUMORS
 PRE-RC PROTEINS AND ONCOGENIC...
 CONCLUDING REMARKS
 REFERENCES
 
To limit replication to a single round per cell cycle, DNA replication can begin only when sufficient DNA replication initiation machinery is recruited to the DNA. The initial recruitment process starts immediately on freshly postmitotic DNA and is known as "licensing" (4) . Licensing begins at replicating origins in early G1 with the formation of pre-RCs, which involves sequential recruitment of the origin recognition complexes (ORCs), the loading factors Cdc6 and Cdt1, and the putative DNA replicative helicase component, MCM complexes, which allow for origin firing and DNA replication initiation at the G1/S transition (Fig. 1 ).


Figure 1
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  		Figure 1. Schematic of pre-RC formation and DNA replication initiation during the cell cycle.

ORCs, composed of six different subunits, are the first proteins to arrive at discrete replicating origins (5) . Unlike in lower eukaryote, Saccharomyces cerevisiae, the replicating origins of other eukaryotes including humans, do not seemingly have unique sequence conservation/specificity but are generally AT-rich. On binding to these AT-rich origins (6) , ORCs serve as "platforms", onto which other pre-RC proteins bind and function. ORCs are AAA+ ATPases that bind to the DNA in an ATP-bound state, an initial attribute that is required for recognition by and association with other pre-RC components for further pre-RC formation. Next, Cdc6, another conserved AAA+ ATPase, recognizes and binds to ATP-bound ORC, resulting in ORC conformational changes that stabilize ORC:origin binding on the DNA. We previously demonstrated that Cdc6 also maintains proper temporal boundaries and origin firing of S-phase replication (7) . Together, Cdc6 and ORC form a stable structure around the origin in preparation for Cdt1 and MCM complex loading (8) . Localization of Cdt1 to the origin is essential for MCM recruitment. Cdt1 activity is regulated by differential stoichiometric binding to DNA replication inhibitor, geminin, and proteolysis (9 10 11) . During S-G2/M, geminin binds Cdt1 at increased stoichiometric ratios and suppresses Cdt1 function, thereby inhibiting rereplication. However, during pre-RC licensing, geminin binds to Cdt1 in a lower stoichiometric ratio, allowing for an "active" form of Cdt1 that can interact with Cdc6 and ORC (12 , 13) . This interaction at origins promotes loading of the MCM complex, a heterohexameric complex consisting of 6 AAA+ ATPase subunits MCM2–7, in a ring-shaped conformation around the chromatin (14) . The colocalization of both Cdt1 and Cdc6 to the pre-RC allows for the localization, but not stable loading of the MCM complex to the replicating origin. After the initial recruitment of MCM to the "immature" pre-RC, two chronological ATPase-dependent switch mechanisms allow for stable, efficient binding of MCM to the origin: first by Cdc6 and then by ORC. First, Cdc6 ATPase activity allows the disassociation of Cdt1 from the pre-RC, a crucial event that allows the MCM ring to close around the DNA (15) . This ATPase activity is followed by ORC ATPase activity that completes the MCM loading reaction and may promote further rounds of MCM loading.

Although necessary, formation of pre-RC is not sufficient to initiate DNA replication. The initiation of DNA replication requires the activation of two S-phase promoting kinases, Cdks (cyclin-dependent kinases) and Ddk (Dbf4-dependent kinase, Cdc7) during the G1/S transition (Fig. 1) . Cdks and Ddk phosphorylate and activate pre-RCs, which promotes the loading of MCM10, Cdc45, GINS, thereby triggering origin firing (16 17 18 19 20 21 22) . It is thought that activation of the helicase activity of MCM by Cdks and Ddk is one of the crucial steps for initiation, although the exact mechanism by which MCM helicase unwinds DNA has yet to be determined (16 , 21 22 23 24 25) . Phosphorylation of ORC, Cdc6, Cdt1, and MCM proteins also results in the inactivation and/or disassociation of these proteins from the origin, nuclear export, and proteosomal degradation, ultimately converting the pre-RC into a "post-RC" (postreplicative complex) state to prevent origins from "relicensing" (9 , 12 , 13 , 26 27 28 29 30 31 32 33) . Thus, the precise regulation of pre-RC formation, as well as activation and inactivation restrict DNA replication to once and only once per cell cycle.


   PRE-RC PROTEINS AND TUMORS
TOP
 ABSTRACT
 INTRODUCTION
 PRE-RC PROTEINS AND RESTRICTION...
 PRE-RC PROTEINS AND TUMORS
PRE-RC PROTEINS AND ONCOGENIC...
 CONCLUDING REMARKS
 REFERENCES
 
Proper orchestration of pre-RC and DNA replication proteins guarantees faithful initiation of DNA replication, and insufficient activation or overactivation of these proteins can result in abnormal DNA replication that can promote genomic instability and subsequent tumorigenesis. Thus, it is not surprising that several of these proteins are deregulated in cancer. Pre-RC and DNA replication proteins were observed to be significantly up-regulated in both cancer cell lines and neoplastic/dysplastic tissues in comparison to their respective normal counterparts (Table 1 ). For instance, Cdc6 and Cdt1 were observed to be greatly up-regulated in cervical, lung, and brain cancers. MCM2 up-regulation was observed in oligodendriomas, as well as breast, esophageal, renal, and lung cancers, while increased MCM5 was also observed in cervical and esophageal cancers. Increased ORC expression was detected in cervical cancer cell lines and other transformed cell lines. Other pre-RC components or regulators, such as geminin, were up-regulated in breast, colorectal cancers, oligodendriomas, and astrocytic brain tumors. GINS expression has been recently shown to be increased in cholangiocarcinoma, and Cdc7 levels were up in myeloid, lymphocytic, cervical, colorectal and lung cancers, and melanomas. "Up-regulation" of these proteins refers not only to per cell expression levels but, importantly, also to the abnormal spatial distribution changes of these proliferating cells. In normal tissues, pre-RC proteins are restricted to proliferating cells directly above a defined epithelial basal layer. In contrast, such topological restriction is abolished in transformed tissues, as the pre-RC protein overexpressing cells invade the upper layers of normally low/nonproliferating cells (34) . Figure 2 shows such abnormal invasion of cells overexpressing MCM2 into the upper strata of esophageal tumor epithelium, in contrast to the restricted localization of these cells in adjacent normal tissue samples. Overexpression of pre-RC proteins also correlates with increasing tumor grade and poor prognosis (35) . In light of these pathophysiological associations, use of the expression signatures of pre-RC proteins as tumor diagnostic markers is currently being explored. However, these findings also pose long-standing questions: Are pre-RC proteins oncogenic? If they are oncogenic, how do they contribute to the transformation process? Recent functional studies indicate that, other than simply indicative of rapid cell proliferation, pre-RC proteins also play direct and active roles in tumorigenesis.


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  		Table 1. Comparison of current data on tumor/cancer cell expression, functional analysis, and direct oncogenic contribution of indicated individual pre-RC components


Figure 2
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  		Figure 2. Analysis of MCM2 expression in a human esophageal tumor tissue and its adjacent tissue by immunohistochemistry using anti-MCM2 antibody. A) MCM2 expression in the normal adjacent tissue is restricted to a narrow region of epithelial (EP) substrata, located above a precise basal cell layer (*) that is adjacent to the lamina propria (LP). Note: the defined basal layer does not stain positive for MCM2 expression. B) In contrast, definition of the basal layer is lost in the tumor section, as MCM2 expressing cells invade upward past their normal epithelial boundaries. (L) represents lumen. Method: Deparaffinized sections were quenched for endogenous peroxidase activity in 0.3% hydrogen peroxide in methanol. The slides were then immunostained with anti-MCM2S1 antibodies (21) overnight, then washed and further immunostained with biotinylated anti-rabbit antibody (Vector laboratories) and diaminobenzidene (1 mg/ml) and 0.03% hydrogen peroxide.


   PRE-RC PROTEINS AND ONCOGENIC POTENTIAL
TOP
 ABSTRACT
 INTRODUCTION
 PRE-RC PROTEINS AND RESTRICTION...
 PRE-RC PROTEINS AND TUMORS
 PRE-RC PROTEINS AND ONCOGENIC...
CONCLUDING REMARKS
 REFERENCES
 
The functional ablation or overexpression of pre-RC proteins results in significant cell cycle perturbation that ultimately may contribute to oncogenesis. Studies that functionally ablated pre-RC proteins in several organisms, including humans (via siRNA, antibody/peptide neutralization, dominant negative, or temperature sensitive mutants, etc.), have resulted in a variety of detrimental cell cycle outcomes, including inhibition of DNA replication initiation and perturbation of cell cycle progression and/or cell viability. For instance, the ablation of ORC2, Cdt1, or Cdc7 in mammalian cells (36 37 38 39 40) ; MCM5 in zebrafish (41) ; MCM3, 4 or 7 in fission yeast (42) ; or ORC6 in budding yeast results in similar DNA replication inhibition (43) , cell cycle arrest, and/or cell death, although the molecular mechanisms of these effects have not been determined in detail (Table 1) .

Recently we have shown that the different phenotypes arise from lack of pre-RC proteins in different cell cycle phases. Insufficient Cdc6 function in G1 phase of human tumor cells causes inhibition of the initiation of DNA replication and cell cycle arrest in G1, whereas insufficient Cdc6 function in S phase inhibits new origin firing, but not elongation, perturbing normal S-phase DNA replication. The resulting incomplete DNA replication seems to bypass S-phase checkpoints and cause mitotic lethality in cancer cells (7) . Yeast exhibits a similar "reductional anaphase" phenotype when Cdc6p or Cdc18 (the Schizosaccharomyces pombe homologue of Cdc6) was suppressed in S phase (44 , 45) . Similar observations have been made of Orc subunits depletion and inhibition of S-phase promoting kinases in yeast and mammalian cells, which also resulted in aberrant DNA replication/S-phase progression/checkpoint response as well as abnormal mitosis and cell death (46 47 48 49) . Collectively, these results indicate that pre-RC proteins play crucial roles in G1 origin licensing and in proper S phase DNA replication and checkpoint responses that are essential for S-phase progression and DNA segregation in mitosis.

While inhibited DNA replication and slowed S-phase progression are expected from pre-RC insufficiency, the unusual and catastrophic events in mitosis observed to result from insufficient replication licensing have raised questions about whether such phenotypes reflect a more complicated replication function of pre-RC proteins, or some other kind of function altogether. Resulting cell death might be explained by the implicated involvement of pre-RC proteins in checkpoint signaling: insufficient pre-RC function may compromise cellular surveillance that maintains chromosomal integrity, and thus ultimately cell viability (48 , 50 , 51) . Recently, Hermand and Nurse eloquently showed that Cdc18 serves as a chromatin anchor that directly binds to Rad26 (S. pombe homologue of ATRIP) on the Rad3-Rad26 (S. pombe homologue of ATR-ATRIP) checkpoint complex (52) . Loss of Cdc18 results in compromised S-phase checkpoint response, aberrant DNA replication and inappropriate mitotic entry that is consistent with our observations of mitotic catastrophe after S-phase depletion of Cdc6 in mammalian cancer cells (7) . The mechanism provided by Hermand and Nurse, together with the observations of the Cdc6 checkpoint function in higher eukaryotes (53 , 54) , offer compelling evidence indicating that pre-RC proteins are essential not only for accurate DNA replication/S-phase progression but also for effective S-phase checkpoint signaling and genomic stability.

Consistently, Woodward et al. showed that partial loss of MCMs in Caenorhabditis elegans results in hypersensitivity to otherwise nontoxic concentrations of hydroxyurea. These results demonstrate that insufficiency of pre-RC proteins alone can result in atypical sensitivity to genotoxic insult (55) . It is thought that insufficient pre-RC function can promote oncogenesis in vivo by contributing to genomic instability. Tumorigenesis in vivo likely involves hypomorphic deletion or mutation rather than homozygous deletion or dominant negative mutation of pre-RC proteins, which would result in robust cell cycle arrest/cell death. Remarkable evidence of this notion was presented in the recent publication of Shima et al., which demonstrated that a N-ethyl-N-nitrosourea (ENU)-induced hypomorphism, Chaos3, in the MCM4 allele(s) directly results in a high occurrence of mammary adenocarcinomas and increased sensitivity and DNA breakage in response to replication stress in both mammalian animal and cell models (56) . This finding, together with the other above recent data, demonstrates that partial loss of function of a single pre-RC component can directly lead to genomic instability—a long-debated driving force of tumorigenesis (57 , 58) .

Equally as deleterious as loss of pre-RC function, gain of pre-RC function can wreak havoc on proper DNA synthesis and may spark early tumorigenic events. For instance, the overexpression of ORC1 in yeast (59) , or of Cdc6, Cdc7, MCM7, or Cdt1 in various other eukaryotic cells (60 61 62) , including human cells, results in detectable abnormal DNA rereplication and S-G2/M phase checkpoint activation (Table 1) (63 , 64) . Recently, Green et al. have demonstrated in yeast that these differential phenotypes are the result of nonredundant cell cycle mechanisms (65) . Similar to the notion of partial loss of function of pre-RC proteins during oncogenesis, they suggest that in instances of gain of pre-RC function, it is subtle pre-RC deregulation that produces low levels of rereplication, which is a likely proponent of tumorigenesis. This low-level magnitude of rereplication may slip by the surveillance of replication checkpoint machinery, thus causing genomic instability and tumorigenesis. However, if levels of rereplication are high enough to trigger DNA replication checkpoint activation, it may be that the normal DNA checkpoint cell cycle arrest is overridden by the overexpression of replication promoting proteins. Whichever the case may be, abnormal rereplication has been thought to contribute to genomic instability and tumorigenesis. Consistent with this notion, Davidson et al. showed that overabundance of Cdt1 in Xenopus egg extracts resulted in DNA rereplication and detectable chromosomal fragmentation (66) . Furthermore, Tatsumi et al. recently showed that actual genomic ploidy is increased in mammalian cells that overexpress Cdt1 (67) , indicating that gain of pre-RC function causes direct chromosomal damage. Since pre-RC proteins interact with checkpoint/damage response signaling, it is conceivable that excess pre-RC components might directly sequester and diminish interacting checkpoint protein signaling (68 69 70) . Diminution of checkpoint signaling, combined with rereplication, could trigger oncogenesis. Supporting such gain of function involvement in oncogenesis, groups have shown that overexpression of Cdt1 in NIH3T3 cells can promote cell transformation and that Cdt1 transgenic mice develop lymphoblastic lymphoma in the absence of p53 (71) . Additionally, a transgenic mouse model with deregulated expression of MCM7 protein in the basal layer of the epidermis shows that MCM7 contributes to oncogene-driven tumorigenesis (62) . The direct mechanism(s), by which individual pre-RC deregulation drives oncogenic transformation, however, remained a mystery—until a recent publication by Gonzalez et al.

Gonzalez et al. (72) published their striking study showing the direct mechanistic involvement of Cdc6 in oncogenesis. They show that overexpression of Cdc6 in mammalian cells results in the direct and specific hypermethylation of the tumor suppressor INK4/ARF locus. Cdc6 binds to a replication origin, which also serves as a transcriptional element, in the INK4/ARF locus and Cdc6 binding to the origin/transcriptional element causes recruitment of histone deacetylases, resulting in hypermethylation and heterochromatinization of the INK4/ARF locus and repression of p14ARF, p16INK4A, and p14INK4B expression. As p14ARF, p16INK4A, and p14INK4B are three critical cell cycle inhibitors, inhibition of expression of these proteins relieves much negative cell cycle regulation. Such derepression of cell cycle progression, accompanied by overexpression of Cdc6, enhances cell proliferation and thus contributes to genomic instability and tumorigenesis. Consistently, Gonzalez et al. also show that, like ablation of INK4A expression, overexpression of Cdc6 can cooperate with Ras oncogene to transform cultured mouse embryonic fibroblasts (MEFs). Gonzalez et al. go further to show an inverse correlation between expression levels of Cdc6 and p16INK4A protein in human nonsmall cell carcinoma sections. In contrast, there is a lack of correlation between expression levels of proliferation marker, Ki67, and high levels of Cdc6. Thus, overexpression can render Cdc6 oncogenic by its specific silencing of critical tumor suppressors, such as p16INK4A. Juxtaposed with the recent findings of Hermand and Nurse (52) , that Cdc6 may serve as a chromatin anchor for the ATR-ATRIP complex, it is conceivable that aberrant overexpression of Cdc6 could also further deregulate cell cycle progression and genomic fidelity by sequestering the ATR-ATRIP complex, thereby abrogating proper S-phase checkpoint signaling.

Conversely, in light of the results by Shima et al., it is plausible that partial lack of individual pre-RC protein function in vivo may have significant regulatory gene transcription consequences, in addition to the genomic instability and increased tumor incidence that they observed. Essential gene expression during the ongoing cell cycle requires careful coordination, and this stringent balancing act is suggested to be a level of sensitive and rapid cellular response for growth and proliferation (73) . Thus, as a result of abnormal pre-RC function, just the correct amount of genomic instability, compounded by uncontrolled cell cycle progression, is likely an effective recipe for oncogenic transformation. Insufficiency of pre-RC function in tumor cells seems to bypass DNA damage/repair responses, which would induce cell cycle arrest in normal cells. Overexpression of pre-RC components has also yielded checkpoint activation (32 , 37 , 53 , 55) , a response to anomalous pre-RC function that presumably keeps normal cells from perpetuating problematic defects (39 , 50 , 74) . Whether such abnormal bypass and cell cycle progression in tumor cells requires additional anomalies, such as p53 or Rb deficiencies, is unclear. Although, in the case of pre-RC overexpression, p53 and ATR/ATM deficiency or signal abrogation clearly potentiate oncogenic effects. Premalignant/early phase cancer tissues exhibit activation of DNA replication checkpoints that seem to correlate with latency of disease progression, a latency that might end when subpopulations of checkpoint-arrested cancer cells finally overcome these cell-cycle barriers via gain or loss of function of DNA replication regulating proteins (72 , 75 76 77) . The replication checkpoint circumvention by cancer cells may also explain the abnormal cell cycle progression during situations of pre-RC deficiency. As pre-RC proteins have been implicated in DNA checkpoint response pathways, deficiency of pre-RC proteins could contribute to checkpoint circumvention (68 , 69 , 78) . Of important note are several recent observations of nonlethal cell cycle arrest by normal cells during pre-RC deficiency (37 , 39 , 40 , 50) . This suggests that the cell death observed in cancer cells in the same situation may be the result of such evasion or uncoupling of these same checkpoint mechanisms that are otherwise intact in normal cells. Clearly more investigation is warranted, particularly to determine how cells sense imbalanced pre-RC function, and whether pre-RC components, themselves, may actively comprise this signaling pathway. Together, these data indicate that balanced and sufficient pre-RC function, as well as checkpoint response, directly impacts genomic stability and oncogenesis (Fig. 3 ).


Figure 3
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  		Figure 3. Systematic representation of pre-RC/DNA replication proteins and oncogenesis. For details, see text.


   CONCLUDING REMARKS
TOP
 ABSTRACT
 INTRODUCTION
 PRE-RC PROTEINS AND RESTRICTION...
 PRE-RC PROTEINS AND TUMORS
 PRE-RC PROTEINS AND ONCOGENIC...
 CONCLUDING REMARKS
REFERENCES
 
The role of pre-RC proteins in oncogenic transformation raises important questions, such as: How do pre-RC proteins come to be deregulated in the first place? Which pre-RC proteins can selectively target and regulate gene expression? How and when do they do so? In the chronological context of oncogenesis, deregulated pre-RC proteins may contribute to early oncogenic events, as the silencing of p16INK4A has been shown to be an early event in carcinogenic transformation (75) . It is conceivable that such silencing may be, at least in part, the result of early deregulated and elevated levels of pre-RC components. Although exactly what leads to an early deregulation of pre-RC components remains to be demonstrated, current evidence highlights the importance of pre-RC components in carcinogenesis, suggesting that pre-RC components could have significant diagnostic and therapeutic value (50 , 74) . If it is loss of cellular response to deregulated pre-RC function that promotes tumorigenesis, then the therapeutic targeting of pre-RC proteins may inhibit disease progression or sensitize cancer cells to cell death. Further investigation into the oncogenic properties of pre-RC proteins will elucidate early transformation events that may be significant for prevention and therapy, as well as in our understanding of the regulation of DNA replication and the initiation of cancerous transformation.


   ACKNOWLEDGMENTS
 
This work was supported by predoctoral training grant 2T32 CA77109–06A2 to E.L., by NIH grants CA97950 and GM67859 to W.J. and by National Key Basic Research Program of China (973–2002CB513101) to S-H.L. and W.J.

Received for publication April 25, 2007. Accepted for publication June 27, 2007.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PRE-RC PROTEINS AND RESTRICTION...
 PRE-RC PROTEINS AND TUMORS
 PRE-RC PROTEINS AND ONCOGENIC...
 CONCLUDING REMARKS
 REFERENCES
 

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