Cell Cycle and Cervical Carcinoma p14ARF and p16INK4A is strongly associated with HPV-positive cervical cancers and that reduced expression of p14ARF and p16INK4A is correlated with HPV-negative cervical cancers.86 These find- ings may indicate that impaired p14ARF and p16INK4A mRNA expression contribute to tumor development in HPV-negative cervical cancers by failure to support p53 and Rb instead of their inactivation by HPV E6 and E7. In human fibroblasts, it has been shown that p14ARF-induced cell cycle arrest is p53- depen- dent and is abrogated by the co-expression of the HPV E6 protein.89,90 Therefore, upregulation of p14ARF is a consequence of inactivation of p53 rather than a sign of cell cycle inhibition. Brooks et al. demonstrated that the expression levels of p14ARF were clearly elevated in 84% of cervical cancers and 79% of CIN III relative to matched normal tissue by RT-PCR.91 Interestingly, immu- nocytochemical analysis revealed that p14ARF was abundantly expressed in almost all cases of both cervical SCC and CIN III and was overexpressed with p73 in a great majority of cases. The frequent simultaneous overexpression of p14ARF with p73 is consistent with E2F1-driven expression of both genes. p73 has structural and functional homo- logies to p53, including sequence-specific DNA binding and transactivation.92 MDM-2 The cellular protein MDM-2 is encoded by the mdm-2 oncogene and has been shown to bind to the p53 protein, inactivating its ability to function as a transcription factor.93 MDM-2 is a zinc finger protein composed of 491 amino acids. The MDM-2 protein interaction with p53 to form the p53/ MDM-2 complex covers the p53 N-terminal acidic or activation domain required for activation of transcription.94 This is the same region of the p53 DNA binding domain bound by the HPV E6 protein, thus blocking transcriptional activation. Whether MDM2 acts solely through the inhibition of p53 or has additional activities remains to be determined. The mdm-2 gene can be de-regulated in soft- tissue sarcomas, bladder carcinomas, renal-cell carcinomas, and breast carcinomas.95-97 Dellas et al. analyzed the altered patterns of MDM-2 and p53 expression in cervical neoplasms and detected MDM-2 as well as p53 in all histological grades of cervical neoplasia.95 The fraction of positive cells for MDM-2 ranged from 0 to 31% in CIN cases and from 0 to 81% in invasive carcinomas. The percentage of p53-stained neoplastic cells ranged from 0 to 40% in CIN cases and from 0 to 69% in invasive carcinomas. Dellas et al. de- monstrated that aberrant MDM-2 and p53 expres- sion is frequently found in cervical neoplasia. Skomedal et al. found that MDM2 may protect against HPV-induced p53 protein degradation.95 In contrast to the above-mentioned results, Lie et al. reported that there is no correlation between HPV status and expression of the cell cycle regu- lators p53, MDM-2, and p21.54 Inactivation of p21 and p53 protein may be important, and MDM-2 abnormalities seem to play a minor role in the development of high-grade CIN. Ikenberg et al. found that p53 mutation and amplification of the mdm-2 oncogene are rare, even in HPV-negative primary cervical carcinomas.98 In contrary, Tsuda et al. found strong expression of MDM-2 was higher in invasive cancers (32.1%) than in CINs (7.1%).12 Troncone et al. reported that immunosta- ining for MDM-2 and p21WAF1 was not abrogated in invasive cervical cancer by high-risk HPV genomic sequences, and there were no significant differences in the expression of p53, MDM-2, and p21WAF1 between the HPV DNA-positive and -negative groups, as similar levels of expression were observed.99 p53 The TP53 gene, present on chromosome 17p, acts as a tumor suppressor gene, controlling entry into the S-phase of the cell cycle, and p53 plays many important roles in cell proliferation. Muta- tion of this gene inactivates its suppressor activity and is related to tumor progression.100 The p53 tumor suppressor gene encodes a transcriptional factor central in the regulation of cell growth, DNA repair, and apoptosis induction. Its activity requires the induction of several target genes, including MDM-2 and p21WAF1.99 The TP53 gene is lost or mutated in over 50% of human cancers. However, in contrast to many other human tumor forms, TP53 mutations are only rarely detected in cervical cancer.101,102 A great amount of research data suggests that the Yonsei Med J Vol. 46, No. 5, 2005