Yonsei Medical Journal Vol. 46, No. 5, pp. 597 - 613, 2005 Aberrant Cell Cycle Regulation in Cervical Carcinoma Young Tae Kim and Min Zhao Department of Obstetrics and Gynecology, Women's Cancer Clinic, Women's life and Science Institute, Yonsei University College of Medicine, Seoul, Korea. Carcinoma of the uterine cervix is one of the most common malignancies among women worldwide. Human papilloma- viruses (HPV) have been identified as the major etiological factor in cervical carcinogenesis. However, the time lag between HPV infection and the diagnosis of cancer indicates that multiple steps, as well as multiple factors, may be neces- sary for the development of cervical cancer. The development and progression of cervical carcinoma have been shown to be dependent on various genetic and epigenetic events, especially alterations in the cell cycle checkpoint machinery. In mam- malian cells, control of the cell cycle is regulated by the activity of cyclin-dependent kinases (CDKs) and their essential activating coenzymes, the cyclins. Generally, CDKs, cyclins, and CDK inhibitors function within several pathways, inclu- ding the p16INK4A-cyclin D1-CDK4/6-pRb-E2F, p21WAF1- p27KIP1-cyclinE-CDK2, and p14ARF-MDM2-p53 pathways. The results from several studies showed aberrant regulation of several cell cycle proteins, such as cyclin D, cyclin E, p16 INK4A, p21WAF1, and p27KIP1, as characteristic features of HPV- infected and HPV E6/E7 oncogene-expressing cervical carci- nomas and their precursors. These data suggested further that interactions of viral proteins with host cellular proteins, particularly cell cycle proteins, are involved in the activation or repression of cell cycle progression in cervical carcino- genesis. Key Words: Cell cycle, cervical carcinoma, cyclin Received July 6, 2005 This study was supported by Yonsei women's cancer biomarker center and supported by the Brain Korea (BK) 21 Project for Medi- cal Sciences, Yonsei University, 2005 and supported by a grant from the Korean Health 21 R&D Project, Ministry of Health Welfare, Republic of Korea (0412-CR01-0704-0001). Reprint address: requests to Dr. Young Tae Kim, Department of Obstetrics and Gynecology, Yonsei University College of Medi- cine, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-752, Korea. Tel: 82-2-2228-2230, Fax: 82-2-313-8357, E-mail: ytkchoi@yumc. yonsei.ac.kr INTRODUCTION Carcinoma of the uterine cervix is one of the most common malignancies among women world- wide. The incidence of cervical carcinoma is on the decline, but still 370,000 new cases and 190,000 resulting deaths occur each year.1 The develop- ment of cervical carcinoma is a multi-step carcino- genesis. However, the steps in the progression from low-grade cervical intraepithelial neoplasia to carcinoma remain unknown. Human papillo- maviruses (HPVs) have been identified as the major etiological factor in cervical carcinogenesis.2 Epidemiological evidence indicates that the ma- jority of cervical neoplasia is attributable to HPV infection. Also, although certain HPV genes are capable of immortalization and can cooperate in the process of transformation, not all non-invasive lesions progress to the full malignant phenotype. This suggests that other cofactors are required. Recently, it has become increasingly clear that HPVs replicate by interfering with normal cell cycle control mechanisms. Malignant transforma- tion is also intimately related to these processes, and it is likely that the oncogenic potential of papillomaviruses lies in their ability to alter cell cycle checkpoints, thereby leading to the accumu- lation and transmission of genetic abnormalities. As we know, the E6 and E7 oncoproteins of high- risk HPVs, particularly HPV 16 and 18, bind respectively to the p53 and Retinoblastoma (Rb) tumor suppressor proteins, which are involved in the regulation of growth control. Moreover, the E6 proteins of high-risk HPVs bind more effectively to the p53 protein, leading to their degradation via a ubiquitin-mediated pathway, than those of lower-risk HPVs. Yonsei Med J Vol. 46, No. 5, 2005