Alteration of cell cycle in cervical tumor associated with human papillomavirus: cyclin-dependent kinase inhibitors.
The ability of viral oncoproteins to subvert cell cycle checkpoints may constitute a mechanism by which viral oncoproteins induce genetic instability. HPV 16 E6 and E7 disrupt cell cycle checkpoints, particularly affecting nearly all cyclin-dependent kinase inhibitors linked to the G1- and G2- checkpoints, in each case by means of a different mechanism. HPV 16 E7 shows homology with the pRb binding sites of cyclin D1, which consequently releases E2F. In addition, E7 directly binds to p21, and releases PCNA and other S-phase promoting genes. In turn, released E2F activates cyclin E, and cyclin E accelerates p27 proteolysis as a function of the antagonistic reaction of its own inhibitor. The induction of p16 expression is assumed to be indirectly associated with E7, which is upregulated only after prolonged inactivation of Rb. HPV 16 E6 decreased the fidelity of multiple checkpoints controlling both entry into and exit from mitosis, with the mechanism of p53 inactivation. In addition, HPV 16 E6 increased the sensitivity to chemically induced S-phase premature mitosis and decreased mitotic spindle assembly checkpoint function. Alongside the impressive advances made in the understanding of the molecular mechanisms, which HPV disrupts, the validity of these conclusions should be evaluated in the diagnostic and prognostic fields.
Cho
Nam Hoon
NH
Department of Pathology, Yonsei University College of Medicine, C.P.O. Box 8044, Seoul 120-752, Korea. cho1988@yumc.yonsei.ac.kr
Kim
Young Tae
YT
Kim
Jae Wook
JW
D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000032:analysis; D005260:Female; D016193:G1 Phase; D016195:G2 Phase; D006801:Humans; D008840:Microfilament Proteins / Q000032:analysis; D009124:Muscle Proteins; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000473:pathology*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D014412:Tumor Virus Infections / Q000473:pathology*; D002583:Uterine Cervical Neoplasms / Q000473:pathology* / Q000821:virology
C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D018809:Proliferating Cell Nuclear Antigen; C058992:Tagln protein, mouse; D018844:Cyclin-Dependent Kinases