Young Tae Kim and Min Zhao inactivation of p53 is believed to play a major role in the carcinogenesis of the uterine cervix. Two different mechanisms may explain the loss of p53 function in cervical cancer-a somatic gene muta- tion which leads to an inactive form and/or the enhanced protein degradation promoted by the E6 oncoprotein of HPV type 16 and type 18. Horner et al. found that sustained inactivation of the p53 pathway by the E6 protein is required for mainte- nance of the proliferative phenotype of HeLa cervical carcinoma cells.103 Troncone's results are consistent with several other reports, indicating that p53 immunostaining occurs in the vast ma- jority of cervical cancers. This report also confirms that higher p53 protein levels are not dependent on the absence of high-risk viral infection as shown by the similar immunoreactivity scores of the HPV-positive and HPV-negative groups. 99,104,105 Tsuda et al. reported that the frequency of p53 overexpression was 28.6% of 42 CINs and 28.3% of 53 invasive carcinomas.12 On the other hand, some studies indicate that immunohistochemical p53 overexpression is not associated with survival in cervical carcinoma.12,106 Other studies also show that there is no significant relationship between p53 expression and pro- gnosis in squamous cell carcinomas of the uterine cervix. This is explained partly by the presence of HPV. The oncogenic potential of HPV appears to be mediated by the E6 and E7 proteins, which are known to bind and inactivate the p53 and pRb proteins, respectively. Furthermore, the HPV E7 oncoprotein has been shown to abrogate p21 and p27 function.103,106,107 In addition to inactivation of the p53 and pRb proteins, other cell cycle regula- tory proteins may be involved in the carcino- genesis of cervical cancer. Other factors Cyclin A Cyclin A appears in the nucleus precisely at the G1/S transition, accumulates throughout the rest of interphase, and disappears at the beginning of mitosis. Both cyclin E and cyclin A control the progression through the cell cycle primarily by activating CDK2. Cyclin A is important for the G1-S transition, for progression through the S phase and for the G2-M transition. Cyclin A binds Yonsei Med J Vol. 46, No. 5, 2005 to CDK2 in S phase and to CDK1 (cdc2) during the G2-M transition. This complex induces phos- phorylation of pRb and the nuclear membrane protein laminin, augmenting nuclear membrane disruption. Therefore, cyclin A is essential in the G1-S and G2-M phase transitions.108 Forced ex- pression of cyclin A provides anchorage indepen- dence to normal cells, and overexpression of cyclin A is a prognostic factor in different tumor types. The transcription of cyclin A is induced by E2F when it is untethered from pRb by the action of HPV E7 oncoprotein.75 Cyclin A is overex- pressed in cervical intraepithelial neoplasia and SCC compared to normal epithelium.76,79 Van de Putte et al. found overexpression of cyclin A in SCC, consistent with previously described re- sults.57 Zehbe et al. demonstrated an overriding of cyclin-dependent kinase inhibitors by high- and low-risk HPV: cyclin A and p21WAF1/CIP1 were co- expressed in the same cells, mainly in cases of low grade cervical intra-epithelial neoplasia (LCIN).109 This provides strong evidence that the p21WAF1/CIP1 G1 block can be overcome in HPV-infected cells in vivo. This conclusion is further strengthened by the result that cyclin A was never found during the G1 phase of cervical carcinoma-derived cell lines. Cyclin B During the normal cell cycle, cyclin B forms complexes solely with CDK1 (cdc2 or p34cdc2), forming the mitosis-promoting factor, which regu- lates the transition from G2 to M phase.3,110 The mitosis-promoting factor is later translocated from the cytoplasm into the nucleus in late S phase. Recent evidence has shown that p53 regulates a G2 checkpoint through cyclin B: p53 prevents the G2/M transition by decreasing cyclin B protein levels and attenuating the activity of its pro- moter.107 Cho et al. found that cyclin B/p34cdc2 is sig- nificantly increased in HPV-16 or -18 positive cervical lesions, including CIN and SCC, in com- parison with HPV-16 or -18 negative lesions.107 Southern et al. demonstrated that expression of the cyclin B protein was up-regulated and persisted into the upper epithelial layers, in parallel with cyclin A expression, in HSIL infected with human papillomaviruses 16, 31, 33, 51, 58, 66, and 67.77