Young Tae Kim and Min Zhao in cyclin E-positive than in cyclin E-negative squa- mous cervical carcinomas, and Quade et al. found cyclin E staining more frequently in more differ- entiated areas of invasive cancer.74,79 HPV-infected cancer was found to express cyclin E significantly more frequently than HPV-negative cases, but this expression was not related to prognostically im- portant factors including age, tumor size, and tumor type.67 This is in accordance with the only other study on the prognostic significance of cy- clin E in squamous carcinoma. Cyclin E overexpression or over-activity may be the direct result of the presence of the HPV E6 and E7 proteins in invasive disease. The presence of HPV E7 leads to inactivation of pRb and in- creased transcription of cyclin E. The HPV E7 oncoprotein inactivates p27, leading to decreased inhibition of cyclin E.75 Southern et al. reported an up-regulation of cyclin E and cyclin A expression in cases of both low-risk and high-risk HPV infec- tion.76 CDK2 CDK2 probably functions as an effector through phosphorylation of key substrates such as the transcription factor p53, the cell cycle regulating phosphatases cdc25A/cdc25C, MDM2, BRCA1, and the transcription factor E2F1.80 CDK2 can have an apoptosis-sensitizing effect and can arrest the cell cycle at different stages. E-type cyclins (E1 and E2) govern the activity of the single catalytic subunit of CDK2. Unlike various combinations of D-type cyclins that are expressed in different cell types, cyclin E-CDK2 complexes are periodic and maximal at the G1- to S-phase transition.81 Cyclin E-CDK2 also prefer- entially phosphorylates pRb at different sites from the cyclin D-dependent kinases, and these modi- fications may differentially impact on the interac- tions of pRb with E2Fs, histone deacetylases, and other chromatin-remodeling proteins.82 One of the most significant consequences of pRb inactivation is activation of cyclin E/CDK2 subunits, often as a result of increased cyclin E expression. Cyclin E/CDK2 complexes can themselves participate in maintained inactivation of pRb in tumor cells. The HPV oncoprotein E7 may abrogate p21- mediated sequestration of cyclin E and render its catalytic partner CDK2 resistant to p27.83 Expres- Yonsei Med J Vol. 46, No. 5, 2005 sion of CDK2 was observed in parabasal cells of normal squamous epithelium, which was in- versely correlated to p27 expression. Shiozawa et al. revealed that no p27 expression was observed in atypical epithelial cells of SIL with elevated expression of Ki-67, cyclin E, and CDK2.64 The expression of cyclin-dependent kinases (CDK2 and cdc2) was also increased in a considerable number of invasive cervical carcinomas.64,79 In those cases, p27 expression was also high and retained the ability to bind to CDK2, but the p27/ cyclin E/CDK2 complex still possessed phos- phorylating activity.64 CDK2 also regulates the cell cycle through its interactions with cyclin A2; thus its functions extend beyond G1 regulation to govern events in S and G2/M as well. Whereas maximal periodic cyclin E-CDK2 activity is detected at G1/S, low levels of cyclin A-CDK2 activity are first detected in late G1 phase. Consistent with crucial roles for cyclin E/CDK2 downstream of pRb, many tumor cells are ex- tremely sensitive to inactivation of cyclin E/CDK2 whether or not they express pRb. This conclusion has been drawn from a multitude of studies de- monstrating antiproliferative effects of overex- pression of p27Kip1, a protein inhibitor of CDK2, or of dominant-negative CDK2 subunits. Further, injection of antibodies against the CDK2 activators cyclin E and cyclin A blocks proliferation, as does treatment of many different cells with CDK2 inhibitors.84,85 The p14ARF-MDM2-p53 pathway p14ARF The CDKN2A gene on human chromosome 9p21 encodes two distinct proteins, p14ARF and p16INK4A, which arise from the same gene by alternative mRNA splicing.86 p14ARF has a mass of 15 kDa and is translated from mRNAs bearing a unique first exon, called 1-beta, located 15 kb upstream of the exon 1-alpha of p16INK4A. Both transcripts share common exons 2 and 3. p14ARF functions as a cell cycle regulator, stopping cell growth at the G1-S border and also at G2-M.87 p14ARF interaction in- hibits the MDM2 oncoprotein, thereby blocking formation of the MDM2-p53 complex and pre- venting MDM2-induced p53 degradation.88 Kanao et al. reported that the overexpression of