Role of the p16 tumor suppressor gene in cancer

被引:574
作者
Liggett, WH
Sidransky, D
机构
[1] Johns Hopkins Hosp, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21287 USA
[2] Johns Hopkins Hosp, Johns Hopkins Oncol Ctr, Baltimore, MD 21287 USA
关键词
D O I
10.1200/JCO.1998.16.3.1197
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Since its discovery as a CDKI (cyclin-dependent kinase inhibitor) in 1993, the tumor suppressor p16 (INK4A/MTS-1/CDKN2A) has gained widespread importance in cancer. The frequent mutations and deletions of p16 in human cancer cell lines first suggested an important role for p16 in carcinogenesis. This genetic evidence for a causal role was significantly strengthened by the observation that p16 was frequently inactivated in familial melanoma kindreds. Since then, a high frequency of p16 gene alterations were observed in many primary tumors. In human neoplasms, p16 is silenced in at least three ways: homozygous deletion, methylation of the promoter, and point mutation. The first two mechanisms comprise the majority of inactivation events in most primary tumors. Additionally, the loss of p16 may be an early event in cancer progression, because deletion of at least one copy is quite high in some premalignant lesions. p16 is a major target in carcino genesis, rivaled in frequency only by the p53 tumor-suppressor gene, Its mechanism of action as a CDKI has been elegantly elucidated and involves binding to and inactivating the cyclin D-cyclin-dependent kinase 4 (or 6) complex, and thus renders the retinoblastoma protein inactive. This effect blocks the transcription of important cell-cycle regulatory proteins and results in cell-cycle arrest. Although p16 may be involved in cell senescence, the physiologic role of p16 is still unclear. Future work will focus on studies of the upstream events that lead to p16 expression and its mechanism of regulation, and perhaps lead to better therapeutic strategies that can improve the clinical course of many lethal cancers, (C) 1998 by American Society of Clinical Oncology.
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页码:1197 / 1206
页数:10
相关论文
共 138 条
[31]   HOMOZYGOTES FOR CDKN2 (P16) GERMLINE MUTATION IN DUTCH FAMILIAL MELANOMA KINDREDS [J].
GRUIS, NA ;
VANDERVELDEN, PA ;
SANDKUIJL, LA ;
PRINS, DE ;
WEAVERFELDHAUS, J ;
KAMB, A ;
BERGMAN, W ;
FRANTS, RR .
NATURE GENETICS, 1995, 10 (03) :351-353
[32]   GROWTH SUPPRESSION BY P18, A P16(INK4/MTS1)-RELATED AND P14(INK4B/MTS2)-RELATED CDK6 INHIBITOR, CORRELATES WITH WILD-TYPE PRB FUNCTION [J].
GUAN, KL ;
JENKINS, CW ;
LI, Y ;
NICHOLS, MA ;
WU, XY ;
OKEEFE, CL ;
MATERA, AG ;
XIONG, Y .
GENES & DEVELOPMENT, 1994, 8 (24) :2939-2952
[33]   Deletion mapping indicates that MTS1 is the target of frequent deletions at chromosome 9p21 in paediatric acute lymphoblastic leukaemias [J].
GuidalGiroux, C ;
Gerard, B ;
Cave, H ;
Duval, M ;
Rohrlich, P ;
Elion, J ;
Vilmer, E ;
Grandchamp, B .
BRITISH JOURNAL OF HAEMATOLOGY, 1996, 92 (02) :410-419
[34]  
Hall M, 1996, ADV CANCER RES, V68, P67, DOI 10.1016/S0065-230X(08)60352-8
[35]  
Hara E, 1996, MOL CELL BIOL, V16, P859
[36]   SOMATIC MUTATIONS OF THE MTS (MULTIPLE TUMOR-SUPPRESSOR)-1 CDK41 (CYCLIN-DEPENDENT KINASE-4 INHIBITOR) GENE IN HUMAN PRIMARY NONSMALL CELL LUNG CARCINOMAS [J].
HAYASHI, N ;
SUGIMOTO, Y ;
TSUCHIYA, E ;
OGAWA, M ;
NAKAMURA, Y .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1994, 202 (03) :1426-1430
[37]   RULES TO REPLICATE BY [J].
HEICHMAN, KA ;
ROBERTS, JM .
CELL, 1994, 79 (04) :557-562
[38]  
Heinzel PA, 1996, INT J CANCER, V68, P420, DOI 10.1002/(SICI)1097-0215(19961115)68:4<420::AID-IJC3>3.0.CO
[39]  
2-2
[40]  
HERBERT J, 1994, BLOOD, V84, P4038