GROWTH ARREST BY INDUCTION OF P53 IN DNA DAMAGED KERATINOCYTES IS BYPASSED BY HUMAN PAPILLOMAVIRUS-16 E7

被引:249
作者
DEMERS, GW
FOSTER, SA
HALBERT, CL
GALLOWAY, DA
机构
[1] Cancer Biology Program, Fred Hutchinson Cancer Res. Center, Seattle, WA 98104, 1124 Columbia Street
关键词
D O I
10.1073/pnas.91.10.4382
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Cellular tumor suppressors p53 and Rb play an important role in controlling cell proliferation. Inactivation of these tumor suppressor proteins can occur by gene mutation or by association with oncoproteins from the small DNA tumor viruses. One function of p53 is in regulating cell cycle check-point control after DNA damage. To dissect the pathways by which p53 and Rb may act, the E6 and E7 oncogenes of human papillomavirus (HBV) types 6 and 16 were introduced into primary human epithelial cells by retroviral transfer vector, and cells were assayed for growth arrest after DNA damage induced by actinomycin D. The E6 or E7 oncogenes from the low-risk HPV6 had no affect on growth arrest, p53 protein levels increased, Rb protein levels decreased, and Rb was predominantly in the hypophosphorylated state similar to vector-infected cells. Either the E6 or the E7 oncogene from the high-risk HPV16 abrogated growth arrest. Cells expressing HPV16 E6 (16E6) were severely reduced in p53 protein levels that did not increase detectably after DNA damage, Rb protein levels did not decrease, and hyperphosphorylated Rb was present. After DNA damage in cells expressing 16E7 p53 levels increased, and Rb protein levels decreased; however, Rb was predominantly in the hyperphosphorylated state. Even though p53 protein levels increased in response to DNA damage in cells expressing 16E7, G(1) growth arrest was bypassed. This suggests that the circuitry controlling the growth arrest signal after DNA damage may be interconnected between the p53 and Rb pathways.
引用
收藏
页码:4382 / 4386
页数:5
相关论文
共 47 条
  • [1] PHOSPHORYLATION OF THE RETINOBLASTOMA GENE-PRODUCT IS MODULATED DURING THE CELL-CYCLE AND CELLULAR-DIFFERENTIATION
    CHEN, PL
    SCULLY, P
    SHEW, JY
    WANG, JYJ
    LEE, WH
    [J]. CELL, 1989, 58 (06) : 1193 - 1198
  • [2] REQUIREMENT FOR A FUNCTIONAL RB-1 GENE IN MURINE DEVELOPMENT
    CLARKE, AR
    MAANDAG, ER
    VANROON, M
    VANDERLUGT, NMT
    VANDERVALK, M
    HOOPER, ML
    BERNS, A
    RIELE, HT
    [J]. NATURE, 1992, 359 (6393) : 328 - 330
  • [3] CRAIG RW, 1984, CANCER RES, V44, P2421
  • [4] SV40 LARGE TUMOR-ANTIGEN FORMS A SPECIFIC COMPLEX WITH THE PRODUCT OF THE RETINOBLASTOMA SUSCEPTIBILITY GENE
    DECAPRIO, JA
    LUDLOW, JW
    FIGGE, J
    SHEW, JY
    HUANG, CM
    LEE, WH
    MARSILIO, E
    PAUCHA, E
    LIVINGSTON, DM
    [J]. CELL, 1988, 54 (02) : 275 - 283
  • [5] ELEVATED WILD-TYPE P53 PROTEIN-LEVELS IN HUMAN EPITHELIAL-CELL LINES IMMORTALIZED BY THE HUMAN PAPILLOMAVIRUS TYPE-16 E7 GENE
    DEMERS, GW
    HALBERT, CL
    GALLOWAY, DA
    [J]. VIROLOGY, 1994, 198 (01) : 169 - 174
  • [6] HETEROGENEITY OF THE HUMAN PAPILLOMAVIRUS GROUP
    DEVILLIERS, EM
    [J]. JOURNAL OF VIROLOGY, 1989, 63 (11) : 4898 - 4903
  • [7] MICE DEFICIENT FOR P53 ARE DEVELOPMENTALLY NORMAL BUT SUSCEPTIBLE TO SPONTANEOUS TUMORS
    DONEHOWER, LA
    HARVEY, M
    SLAGLE, BL
    MCARTHUR, MJ
    MONTGOMERY, CA
    BUTEL, JS
    BRADLEY, A
    [J]. NATURE, 1992, 356 (6366) : 215 - 221
  • [8] HOMOLOGOUS SEQUENCES IN ADENOVIRUS E1A AND HUMAN PAPILLOMAVIRUS E7 PROTEINS MEDIATE INTERACTION WITH THE SAME SET OF CELLULAR PROTEINS
    DYSON, N
    GUIDA, P
    MUNGER, K
    HARLOW, E
    [J]. JOURNAL OF VIROLOGY, 1992, 66 (12) : 6893 - 6902
  • [9] THE HUMAN PAPILLOMA VIRUS-16 E7-ONCOPROTEIN IS ABLE TO BIND TO THE RETINOBLASTOMA GENE-PRODUCT
    DYSON, N
    HOWLEY, PM
    MUNGER, K
    HARLOW, E
    [J]. SCIENCE, 1989, 243 (4893) : 934 - 937
  • [10] WAF1, A POTENTIAL MEDIATOR OF P53 TUMOR SUPPRESSION
    ELDEIRY, WS
    TOKINO, T
    VELCULESCU, VE
    LEVY, DB
    PARSONS, R
    TRENT, JM
    LIN, D
    MERCER, WE
    KINZLER, KW
    VOGELSTEIN, B
    [J]. CELL, 1993, 75 (04) : 817 - 825