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Cyclin E in human cancers

Department of Pathology, University of Natal Medical School, Durban, South Africa

¹Correspondence: Department of Pathology, University of Natal Medical School, Private Bag 7, Congella 4013, Durban, Kwazulu-Natal, South Africa. E-mail: donnellanr{at}med.und.ac.za

	ABSTRACT

TOP ABSTRACT INTRODUCTION CYCLIN E AND pRB CKIs OTHER MECHANISMS OF S-PHASE... CYCLIN E AND ONCOGENIC... CYCLIN E OVEREXPRESSION IS CYCLIN E A... BREAST CANCER GASTROINTESTINAL MALIGNANCIES HEMATOLOGICAL MALIGNANCIES GENITO-URINARY TRACT CANCERS LUNG CANCER SKIN CANCERS SARCOMAS MISCELLANEOUS CONCLUSION FUTURE DIRECTIONS REFERENCES

 
Regulators of the cell cycle such as cyclin E play an important part in neoplasia. The cyclin E protein forms a partnership with a specific protein kinase. This complex phosphorylates key substrates to initiate DNA synthesis. Cyclin-dependent kinase inhibitors (CKIs) are able to suppress the activity of cyclin E. Various substances (including proteins produced by oncogenic viruses) affect cyclin E directly or indirectly through an interaction with CKIs. These interactions are important in elucidating the mechanisms of neoplasia. They may also provide prognostic information in a wide range of common cancers. Cyclin E may even be a target for treatment of cancers in the future.—Donnellan, R., Chetty, R. Cyclin E in human cancers.

Key Words: cell cycle • cyclins • cyclin-dependent kinase • CKIs

	INTRODUCTION

TOP ABSTRACT INTRODUCTION CYCLIN E AND pRB CKIs OTHER MECHANISMS OF S-PHASE... CYCLIN E AND ONCOGENIC... CYCLIN E OVEREXPRESSION IS CYCLIN E A... BREAST CANCER GASTROINTESTINAL MALIGNANCIES HEMATOLOGICAL MALIGNANCIES GENITO-URINARY TRACT CANCERS LUNG CANCER SKIN CANCERS SARCOMAS MISCELLANEOUS CONCLUSION FUTURE DIRECTIONS REFERENCES

 
NEOPLASIA IS CHARACTERIZED by abnormal regulation of the cell cycle. Although p53 is still the most important cell cycle regulator in human neoplasms, there is growing recognition of the role of the cyclins. The cyclins are an ever-growing group of proteins that form the regulatory subunits in complexes with a specific catalytic protein kinase (cyclin-dependent kinase) partner. The cyclins bind to cyclin-dependent kinases (cdks)² using a conserved 87 amino acid sequence, termed the cyclin box. At present, 10 classes of cyclins (designated A–J) are known; within some classes a number of subclasses (e.g., cyclins D1, D2, and D3) exist, so that in total there are 15 different mammalian cyclins. Recently, there has been a focus on cyclin D1 (1) . This review aims to draw attention to another important G1 phase regulator, cyclin E, which is a 395 amino acid protein (2) derived from a gene on chromosome 19q12–>q13 (3) . Cyclin E contributes to normal cell proliferation and development (4, 5), but its aberrant expression in neoplasia has become the subject of particular interest after the realization that overexpression of cyclin E can accelerate the G1 phase of the cell cycle (6) .

	CYCLIN E AND pRB

TOP ABSTRACT INTRODUCTION CYCLIN E AND pRB CKIs OTHER MECHANISMS OF S-PHASE... CYCLIN E AND ONCOGENIC... CYCLIN E OVEREXPRESSION IS CYCLIN E A... BREAST CANCER GASTROINTESTINAL MALIGNANCIES HEMATOLOGICAL MALIGNANCIES GENITO-URINARY TRACT CANCERS LUNG CANCER SKIN CANCERS SARCOMAS MISCELLANEOUS CONCLUSION FUTURE DIRECTIONS REFERENCES

 
Both cyclin D1 and E drive cell proliferation forward by phosphorylating the product of the retinoblastoma gene (pRB). Hyperphosphorylated pRB then releases bound transcription factors of the E2F family to cause DNA synthesis. Cyclin E is both a regulator and a target of the E2F transcription family in an autoregulatory loop that is necessary for progression from the G1 to the S phase of the cell cycle (7 8 9) (Fig. 1 ). Under normal circumstances, pRB phosphorylation requires cyclin D/cdk4 prior to the action of cyclin E/cdk2 (11, 12) . However, some malignant cells may preferentially use only one cyclin to accomplish the task of phosphorylating pRB, making the other cyclin redundant (13 14 15 16) . In a study using myeloblastic leukemia cell lines, cyclin E appeared more important in cell proliferation whereas cyclin D1 was involved in cell differentiation (17) . The same may apply to other tumors, such as breast carcinomas (18, 19) , but more research is needed to confirm these findings.

View larger version (26K): [in this window] [in a new window]   Figure 1. The cell cycle is divided into four phases: the S phase (during which DNA synthesis occurs) and the M (mitotic) phase are separated by two resting phases: the G1 and the G2 phases. Different combinations of cyclin complexed with cyclin-dependent kinase (cdk) regulate various phases of the cell cycle. Cyclin E joins with cdk2 to regulate the transition from the G1 to the S phase. During the cycle, several checkpoints exist that ensure structural integrity of the genome prior to replication and division. The most notable checkpoint is regulated by p53 in mid-to-late G1 phase (modified from ref 10 ).

	CKIs

TOP ABSTRACT INTRODUCTION CYCLIN E AND pRB CKIs OTHER MECHANISMS OF S-PHASE... CYCLIN E AND ONCOGENIC... CYCLIN E OVEREXPRESSION IS CYCLIN E A... BREAST CANCER GASTROINTESTINAL MALIGNANCIES HEMATOLOGICAL MALIGNANCIES GENITO-URINARY TRACT CANCERS LUNG CANCER SKIN CANCERS SARCOMAS MISCELLANEOUS CONCLUSION FUTURE DIRECTIONS REFERENCES

 
Whether cyclin E (or D1) phosphorylates pRB is dependent on levels of a recently discovered group of molecules, termed the cyclin-dependent kinase inhibitors (CKIs) (20) . As their name suggests, the CKIs are able to bind to and inhibit active cyclin/cdk complexes. CKIs can be divided into two groups based on structure and function: the Kip/Cip proteins (consisting of p21, p27, and p57) and the INK4 proteins (p15, p16, p18, p19). Whereas the INK4 proteins are relatively specific inhibitors of complexes containing the D-type cyclins, the Kip/Cip family can inhibit a wide variety of cyclins. Although all of the Kip/Cip family have been shown to be capable of inhibiting cyclin E (21 22 23) , p21/Cip1 and p27 have attracted the most attention. p21 is an important intermediary molecule because it is under the transcriptional control of p53. Accumulation of normal (wild-type) p53 is known to arrest cells in G1. Its actions on p21 and, thence, cyclin E may clarify the mechanisms involved in G1 phase arrest (Fig. 1) . Increased binding of p21 to cyclin E-Cdk2 is also the mechanism of action for the growth suppression/inhibition of:

BRCA1, a gene important in familial breast and ovarian cancers (24, 25) ;

transforming growth factor ß in head and neck squamous carcinomas (26) ;

cross-linked cell surface anti-immunoglobulin M in human lymphoma cell lines (27) ;

potent prostaglandin A1 analogs in glioma cell lines (28) ;

concanavalin A and phorbol 13-myristate 12-acetate in murine T lymphoma cell lines (29) .

The ability of p27 to inhibit growth in human cancers through interaction with cyclin E-Cdk2 has also been amply demonstrated (23, 30 31 32 33) . Some of the mechanisms of this interaction have been elucidated (34) . Ancillary pathways using p27, such as E-cadherin induced contact inhibition (35) , have now been discovered. Also of note is the demonstrated ability of p27 to act not only as an inhibitor, but also as a target of cyclin E/cdk2 (36) (Fig. 1) .

Although the mechanism of action of -interferon is thought to operate via inhibitory effects on Cdks complexed with cyclin E (37, 38) , it is not yet clear whether this involves any of the CKIs. The observed effect of exogenous and endogenous growth factors such as basic fibroblast growth factor (39) , epidermal growth factor, and cementum-derived growth factor (40) to stimulate cyclin E is also likely to operate via CKIs.

	OTHER MECHANISMS OF S-PHASE INDUCTION

TOP ABSTRACT INTRODUCTION CYCLIN E AND pRB CKIs OTHER MECHANISMS OF S-PHASE... CYCLIN E AND ONCOGENIC... CYCLIN E OVEREXPRESSION IS CYCLIN E A... BREAST CANCER GASTROINTESTINAL MALIGNANCIES HEMATOLOGICAL MALIGNANCIES GENITO-URINARY TRACT CANCERS LUNG CANCER SKIN CANCERS SARCOMAS MISCELLANEOUS CONCLUSION FUTURE DIRECTIONS REFERENCES

 
Recent evidence suggests that cyclin E may be able to promote the S phase by using pathways that do not involve pRB (41 42 43 44) . This was most convincingly demonstrated by Leone et al. (45) when they showed that Myc and Ras coexpression led to cyclin E-dependent kinase activity and S phase induction without pRB phosphorylation. The mechanism of action of Myc and Ras is mainly indirect, by disinhibition rather than direct activation of cyclin E, since Myc and Ras collaboration leads to a dramatic decrease in the levels of p27, one of the CKI proteins known to inhibit cyclin E/cdk2 complexes. Although how Myc, Ras, and activated cyclin E complexes induce the S phase without phosphorylating pRB was not fully explained, it was shown that Myc may bind directly to promoter sequences activating E2F transcription factors. Subsequently, however, Cyclin E/cdk2 complexes have been shown to phosphorylate and thereby activate other transcriptional regulators important in cellular proliferation such as human B-MYB (46) and NPAT (47) . It is likely that we have only scratched the surface and that further interactions between cyclin E and transcription factors will be discovered. However, the scope for research is not restricted to transcription factors. The association of cyclin E with pre-mRNA splicing machinery (48) has opened even more horizons.

	CYCLIN E AND ONCOGENIC VIRUSES

TOP ABSTRACT INTRODUCTION CYCLIN E AND pRB CKIs OTHER MECHANISMS OF S-PHASE... CYCLIN E AND ONCOGENIC... CYCLIN E OVEREXPRESSION IS CYCLIN E A... BREAST CANCER GASTROINTESTINAL MALIGNANCIES HEMATOLOGICAL MALIGNANCIES GENITO-URINARY TRACT CANCERS LUNG CANCER SKIN CANCERS SARCOMAS MISCELLANEOUS CONCLUSION FUTURE DIRECTIONS REFERENCES

 
There is growing support for a relationship between HPV and cyclin E (49 50 51 52 53 54 55) . HPV E7 protein (implicated in carcinogenesis, especially of the uterine cervix) can interact with p21(Cip1) and abrogate p21(Cip1)-mediated inhibition of cyclin A- and E-associated kinase activities (56) . This may be by blocking regions of the p21 molecule important in the sequestration of cyclin E (57, 58) . A similar role has been suggested for cytomegalovirus (CMV), although in addition to inactivation of CKIs, CMV also appears to induce cyclin E directly (59) . Herpesviruses, too, appear to be able to induce cell proliferation by abrogating the effects of the CKIs (60) . By contrast, HIV-1 inhibits cyclin E activity by causing G1 phase arrest, which supposedly fosters viral replication (61, 62) .

	CYCLIN E OVEREXPRESSION

TOP ABSTRACT INTRODUCTION CYCLIN E AND pRB CKIs OTHER MECHANISMS OF S-PHASE... CYCLIN E AND ONCOGENIC... CYCLIN E OVEREXPRESSION IS CYCLIN E A... BREAST CANCER GASTROINTESTINAL MALIGNANCIES HEMATOLOGICAL MALIGNANCIES GENITO-URINARY TRACT CANCERS LUNG CANCER SKIN CANCERS SARCOMAS MISCELLANEOUS CONCLUSION FUTURE DIRECTIONS REFERENCES

 
Accumulation of cyclin E protein in most cases reflects amplification of the gene (13, 63 64 65) , although other mutations have been detected. However, cyclin E is sometimes modified by posttranscriptional mechanisms (66) , so that increased protein expression can occur without mutations in the cyclin E gene. Splice variants that have structural or functional abnormalities in the cyclin box have also been identified (67, 68) . Immunolabeling localizes cyclin E to the nucleus in the majority of neoplasms studied. However, cytoplasmic staining is increasingly being observed, the significance of which is unclear. Although the protein is synthesized and degraded in the cytoplasm, it is ordinarily transferred rapidly to the nucleus where it exerts its functions. Accumulation of cyclin E in the cytoplasm may reflect increased synthesis, decreased degradation, or failure of nuclear transfer. Because, in the latter scenario, cyclin E can have little direct effect on cell division, the conventional wisdom has been to regard as negative those tumors that show cytoplasmic staining in the absence of any nuclear staining. As Albert Einstein pointed out, "It is the theory that decided what can be observed." Our own attempts to examine the factors that control transport of cyclin E in and out of the nucleus have so far met with little success, but clearly this area needs further investigation.

	IS CYCLIN E A DRIVER GENE?

TOP ABSTRACT INTRODUCTION CYCLIN E AND pRB CKIs OTHER MECHANISMS OF S-PHASE... CYCLIN E AND ONCOGENIC... CYCLIN E OVEREXPRESSION IS CYCLIN E A... BREAST CANCER GASTROINTESTINAL MALIGNANCIES HEMATOLOGICAL MALIGNANCIES GENITO-URINARY TRACT CANCERS LUNG CANCER SKIN CANCERS SARCOMAS MISCELLANEOUS CONCLUSION FUTURE DIRECTIONS REFERENCES

 
The question of whether cyclin E is merely a link in the chain of events that lead to cell proliferation or whether it is a driving force in cell replication is difficult to ascertain at present, but appears to be tumor dependent. In some tumors, cyclin E gene amplification and protein accumulation are late events (32, 64, 69, 70) (supporting the former argument), whereas in other neoplasms an increase in cyclin E is observed early in the progression to malignancy (71, 72) . Because extensive networking occurs between the various cell cycle regulators, it is difficult to apportion sole responsibility on any one of them. Thus, when examining the mechanisms in neoplasia, it is often more meaningful to examine cyclin E together with other cell cycle regulators. For instance, high levels of cyclin E may be functionally inactivated by similarly large numbers of CKIs, such as p21. This may be the explanation for the seemingly incongruous association of high cyclin E levels with a good prognosis in cervical adenocarcinoma (73) .

	BREAST CANCER

TOP ABSTRACT INTRODUCTION CYCLIN E AND pRB CKIs OTHER MECHANISMS OF S-PHASE... CYCLIN E AND ONCOGENIC... CYCLIN E OVEREXPRESSION IS CYCLIN E A... BREAST CANCER GASTROINTESTINAL MALIGNANCIES HEMATOLOGICAL MALIGNANCIES GENITO-URINARY TRACT CANCERS LUNG CANCER SKIN CANCERS SARCOMAS MISCELLANEOUS CONCLUSION FUTURE DIRECTIONS REFERENCES

 
The morphological progression from normal and benign breast tissue through ductal carcinoma in situ (DCIS) to invasive ductal carcinoma is associated with accumulating levels of cyclin E (18) . Also, in high-grade DCIS there are significantly more cyclin E-positive cells than in low-grade DCIS (72) . In invasive breast cancers, cyclin E has been found to be overexpressed out of proportion to other markers of cell proliferation (74, 75) , suggesting that dysregulated expression of the gene may contribute to, rather than be a consequence of, increased cell division. Increased expression of cyclin E has been shown to correlate with poor grade (18) and late-stage lesions (74) as well as negative estrogen receptor status (18, 76) . However, whether cyclin E expression is predictive of prognosis independent of standard clinicopathological factors such as tumor size, lymph node, and distant metastases, as well as estrogen receptor status, is not yet clear. It has been shown that cyclin E is associated with a poor prognosis even in node-negative patients (66, 76) , although the strong correlation with negative estrogen receptors may be a confounding variable in these studies. Whether cyclin E alone or in combination with other proteins (such as p27) (77) allows better prognostic stratification than standard clinicopathological parameters needs further study before incorporation into the routine workup of breast cancer patients can be advocated.

	GASTROINTESTINAL MALIGNANCIES

TOP ABSTRACT INTRODUCTION CYCLIN E AND pRB CKIs OTHER MECHANISMS OF S-PHASE... CYCLIN E AND ONCOGENIC... CYCLIN E OVEREXPRESSION IS CYCLIN E A... BREAST CANCER GASTROINTESTINAL MALIGNANCIES HEMATOLOGICAL MALIGNANCIES GENITO-URINARY TRACT CANCERS LUNG CANCER SKIN CANCERS SARCOMAS MISCELLANEOUS CONCLUSION FUTURE DIRECTIONS REFERENCES

 
Different cell cycle regulatory genes are implicated in carcinomas at various sites along the gastrointestinal tract (78) . Cyclin E appears to be more important in stomach and colorectal cancers than in cancers at other sites. The cyclin E gene is amplified in ~15% of human gastric carcinomas, although even greater percentages show increased mRNA and protein levels (64, 70, 79, 80) . High levels of cyclin E (in association with low p21 or p27 levels) correlate with depth of tumor invasion and advanced stage in gastric carcinoma (32, 64, 69, 70, 80) . Recently the combined variable of cyclin E with often coexpressed p53 protein expression has been shown to be of independent prognostic significance in gastric carcinoma (81) . Thus, assessment of cyclin E in preoperative biopsies may provide valuable information in stratifying patients with gastric carcinoma for different treatment protocols.

Cyclin E gene amplification is also apparent in ~10% of colorectal carcinomas, in some instances together with cdk2 gene amplification (63) . At the protein level, colorectal cancers not only show higher levels than adjacent nonneoplastic mucosa (82) but there appears to be a gradual accumulation of cyclin E protein in the morphological progression from adenoma to adenocarcinoma (83) . Cyclin E protein levels also correlate with grade of atypia in adenomas, stage of carcinoma, and p53 and Ki-67 levels (83) .

	HEMATOLOGICAL MALIGNANCIES

TOP ABSTRACT INTRODUCTION CYCLIN E AND pRB CKIs OTHER MECHANISMS OF S-PHASE... CYCLIN E AND ONCOGENIC... CYCLIN E OVEREXPRESSION IS CYCLIN E A... BREAST CANCER GASTROINTESTINAL MALIGNANCIES HEMATOLOGICAL MALIGNANCIES GENITO-URINARY TRACT CANCERS LUNG CANCER SKIN CANCERS SARCOMAS MISCELLANEOUS CONCLUSION FUTURE DIRECTIONS REFERENCES

 
In one study on adult human lymphoblastic leukemia (ALL), it was found that cyclin E protein expression was significantly increased in relapsed samples compared with pretreatment results (84) . However, in another similar study, cyclin E protein expression was not associated with any difference in the duration of relapse-free intervals or the frequency of recurrence in childhood ALL patients (85) . Promyelocytic leukemia (PML) is an important growth-suppressing protein, disruption of which by t(15;17) in acute promyelocytic leukemia plays a critical role in leukemogenesis (86) . PML has been shown to suppress cell growth by increasing cell cycle duration primarily by elongation of G1. One of the ways PML functions is to reduce levels of cyclin E. In an initial study on acute myeloid leukemia, the rates of complete remission and of disease-free survival were low in patients with M4 or M5 leukemia blasts with overexpressed cyclin E (87) . Cyclin E overexpression is not confined to acute leukemias. Chronic lymphocytic leukemia, and Hodgkin's and non-Hodgkin's lymphomas, have also been associated with high levels of cyclin E (33, 88) , although the significance has not been defined. In the 105 lymphomas that Erlanson et al. (33) studied, cyclin E was associated with poor prognosis. However, this association was not apparent on multivariate analysis.

	GENITO-URINARY TRACT CANCERS

TOP ABSTRACT INTRODUCTION CYCLIN E AND pRB CKIs OTHER MECHANISMS OF S-PHASE... CYCLIN E AND ONCOGENIC... CYCLIN E OVEREXPRESSION IS CYCLIN E A... BREAST CANCER GASTROINTESTINAL MALIGNANCIES HEMATOLOGICAL MALIGNANCIES GENITO-URINARY TRACT CANCERS LUNG CANCER SKIN CANCERS SARCOMAS MISCELLANEOUS CONCLUSION FUTURE DIRECTIONS REFERENCES

 
Cyclin E appears to be an important early factor in cervical squamous cell carcinomas (52, 55) through its link with transforming types of human papilloma viruses (as noted above). However, the prognostic significance of cyclin E in squamous cell carcinomas is not yet clear (89) .

Cyclin E immunostaining is a feature of most endometrial carcinomas (90) . As has been demonstrated in breast cancers, an inverse correlation between positive estrogen receptor status and cyclin E immunostaining appears to exist in endometrial carcinomas, but not in adjacent normal or hyperplastic epithelium from the same patients (91) . Although cyclin E is not restricted to neoplastic endometrial disorders, since increased levels of cyclin E are noted during the normal proliferative phase (92) , there does appear to be an accumulation of this protein from normal through simple and complex hyperplasia to malignancy (91, 93) . Although correlations with serous type, grade, and stage have been suggested (91, 93) , the prognostic implications of cyclin E need to be studied in greater detail (90) .

Between 12% (13) and 21% (65) of ovarian cancers show cyclin E amplification, with a slightly higher percentage showing increased protein expression. However, no correlation has been observed between amplification of the cyclin E gene and tumor type, stage, or grade in these tumors.

Cyclin E immunopositivity correlates (together with p53) with high grade and poor prognosis in transitional cell carcinomas of the renal pelvis and ureter (94) . This is not the case in aggressive bilharzial-related bladder cancers, where cyclin D1 appears to be a better prognostic marker even though a high percentage of cases are immunopositive for cyclin E (95) .

	LUNG CANCER

TOP ABSTRACT INTRODUCTION CYCLIN E AND pRB CKIs OTHER MECHANISMS OF S-PHASE... CYCLIN E AND ONCOGENIC... CYCLIN E OVEREXPRESSION IS CYCLIN E A... BREAST CANCER GASTROINTESTINAL MALIGNANCIES HEMATOLOGICAL MALIGNANCIES GENITO-URINARY TRACT CANCERS LUNG CANCER SKIN CANCERS SARCOMAS MISCELLANEOUS CONCLUSION FUTURE DIRECTIONS REFERENCES

 
Normal lung alveolar epithelial cells react to oxidant stress through transforming growth factor-mediated induction of p21 and subsequent inhibition of cyclin E/cdk2 complexes, giving cells time to repair any mutations before the S phase in much the same manner as p53 (96) . On the other hand, neoplastic bronchial epithelial cells generally have high levels of functional cyclin E/cdk2 complexes (97) . Furthermore, it has been shown that those neoplastic cells with greater active cyclin E/cdk2 complexes are more radiosensitive (98) .

	SKIN CANCERS

TOP ABSTRACT INTRODUCTION CYCLIN E AND pRB CKIs OTHER MECHANISMS OF S-PHASE... CYCLIN E AND ONCOGENIC... CYCLIN E OVEREXPRESSION IS CYCLIN E A... BREAST CANCER GASTROINTESTINAL MALIGNANCIES HEMATOLOGICAL MALIGNANCIES GENITO-URINARY TRACT CANCERS LUNG CANCER SKIN CANCERS SARCOMAS MISCELLANEOUS CONCLUSION FUTURE DIRECTIONS REFERENCES

 
Cyclin E has been detected in a number of premalignant skin lesions, but not in a high percentage of squamous cell carcinomas or basal cell carcinomas (71) . Mouse models suggest that the mode of skin carcinogenesis may affect the expression of cyclin E and other cyclins (99) .

	SARCOMAS

TOP ABSTRACT INTRODUCTION CYCLIN E AND pRB CKIs OTHER MECHANISMS OF S-PHASE... CYCLIN E AND ONCOGENIC... CYCLIN E OVEREXPRESSION IS CYCLIN E A... BREAST CANCER GASTROINTESTINAL MALIGNANCIES HEMATOLOGICAL MALIGNANCIES GENITO-URINARY TRACT CANCERS LUNG CANCER SKIN CANCERS SARCOMAS MISCELLANEOUS CONCLUSION FUTURE DIRECTIONS REFERENCES

 
Cyclin E has been detected in a variety of primary human sarcomas as well as sarcoma cell lines (16, 39, 100) . Almost 50% of high-grade osteosarcomas show positive immunostaining for cyclin E protein. In these tumors, there is an association between cyclin E and cell proliferation as detected by Ki-67 (16) . The ability of proliferating osteoblasts to inhibit cell differentiation in adjacent cells involves interaction with cyclin E and may prove useful in delineating the pathways involved in osteosarcomagenesis (101) . In addition, assessment of cyclin E (along with other cell cycle proteins) may be of value in refining treatment protocols in some sarcomas (100) .

	MISCELLANEOUS

TOP ABSTRACT INTRODUCTION CYCLIN E AND pRB CKIs OTHER MECHANISMS OF S-PHASE... CYCLIN E AND ONCOGENIC... CYCLIN E OVEREXPRESSION IS CYCLIN E A... BREAST CANCER GASTROINTESTINAL MALIGNANCIES HEMATOLOGICAL MALIGNANCIES GENITO-URINARY TRACT CANCERS LUNG CANCER SKIN CANCERS SARCOMAS MISCELLANEOUS CONCLUSION FUTURE DIRECTIONS REFERENCES

 
Many cyclins, including cyclin E, are increased in astrocytoma cell lines (102) and some head and neck squamous carcinoma cell lines (103) , but whether this has any bearing on prognosis will have to be studied in primary human tumors. So far there are very few tumors in which cyclin E appears to play little or no role. The exceptions that remain result more from a lack of research than a lack of involvement. For instance, initial indications that thyroid neoplasms did not involve cyclin E pathways (104) are now being eroded (105) .

	CONCLUSION

TOP ABSTRACT INTRODUCTION CYCLIN E AND pRB CKIs OTHER MECHANISMS OF S-PHASE... CYCLIN E AND ONCOGENIC... CYCLIN E OVEREXPRESSION IS CYCLIN E A... BREAST CANCER GASTROINTESTINAL MALIGNANCIES HEMATOLOGICAL MALIGNANCIES GENITO-URINARY TRACT CANCERS LUNG CANCER SKIN CANCERS SARCOMAS MISCELLANEOUS CONCLUSION FUTURE DIRECTIONS REFERENCES

 
Investigation of cyclin E has provided insights into a number of different neoplasms as well as into the process of neoplasia. So far, the main value of cyclin E is in refining prognosis and treatment of patients with a variety of common cancers.

	FUTURE DIRECTIONS

TOP ABSTRACT INTRODUCTION CYCLIN E AND pRB CKIs OTHER MECHANISMS OF S-PHASE... CYCLIN E AND ONCOGENIC... CYCLIN E OVEREXPRESSION IS CYCLIN E A... BREAST CANCER GASTROINTESTINAL MALIGNANCIES HEMATOLOGICAL MALIGNANCIES GENITO-URINARY TRACT CANCERS LUNG CANCER SKIN CANCERS SARCOMAS MISCELLANEOUS CONCLUSION FUTURE DIRECTIONS REFERENCES

 
In the future, cyclin E may become a target for treatment. In this regard, the demonstrated effect of cell surface anti-immunoglobulin M to suppress cyclin E and result in cancer dormancy holds hope (27) . Until then, there are a host of avenues to explore before we can fully appreciate the intricacies of normal and neoplastic cellular processes. One recently opened avenue with intriguing potential is the discovery of a new G1 cyclin that has close structural homology with cyclin E and has thus been designated cyclin E2 (106 107 108) . Other than the deluge of recent publications, perhaps the clearest indication that this is a vibrant field is that cyclin E research continues to provide as many questions as answers. Are there other substrates that are modified by cyclin E/cdk2 phosphorylation? How does this phosphorylation affect movement of proteins between the cellular compartments? What is the role of phosphorylation in targeting proteins for degradation (109) ? In fact, some important questions remain unasked.

As Rudyard Kipling advised:

"I keep six honest serving-men

They taught me all I know;

Their names are What and Why and When

And How and Where and Who"

	FOOTNOTES

 
² Abbreviations: ALL, acute lymphoblastic leukemia; cdk, cyclin-dependent kinase; CKIs, cyclin-dependent kinase inhibitors; CMV, cytomegalovirus; DCIS, ductal carcinoma in situ; PML, promyelocytic leukemia; pRB, retinoblastoma protein.

	REFERENCES

TOP ABSTRACT INTRODUCTION CYCLIN E AND pRB CKIs OTHER MECHANISMS OF S-PHASE... CYCLIN E AND ONCOGENIC... CYCLIN E OVEREXPRESSION IS CYCLIN E A... BREAST CANCER GASTROINTESTINAL MALIGNANCIES HEMATOLOGICAL MALIGNANCIES GENITO-URINARY TRACT CANCERS LUNG CANCER SKIN CANCERS SARCOMAS MISCELLANEOUS CONCLUSION FUTURE DIRECTIONS REFERENCES

 

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