Cyclin D1 overexpression and p53 inactivation immortalize primary oral keratinocytes by a telomerase-independent mechanism

被引:57
作者
Opitz, OG
Suliman, Y
Hahn, WC
Harada, H
Blum, HE
Rustgi, AK
机构
[1] Univ Penn, Div Gastroenterol, Philadelphia, PA 19104 USA
[2] Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA USA
[3] Univ Freiburg, Dept Med, D-7800 Freiburg, Germany
[4] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA
[5] Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA
[6] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA
[7] Univ Penn, Ctr Canc, Philadelphia, PA 19104 USA
[8] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA
关键词
D O I
10.1172/JCI200111909
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
The immortalization of human cells is a critical step in multistep carcinogenesis. Oral-esophageal carcinomas, a model system to investigate molecular mechanisms underlying squamous carcinogenesis, frequently involve cyclin D1 overexpression and inactivation of the p53 tumor suppressor. Therefore, our goal was to establish the functional role of cyclin D I overexpression and p53 inactivation in the immortalization of primary human oral squamous epithelial cells (keratinocytes) as an important step toward malignant transformation. Cyclin D I overexpression alone was found to induce extension of the replicative life span of normal oral keratinocytes, whereas the combination of cyclin DI overexpression and p53 inactivation led to their immortalization. This study also demonstrates that immortalization of oral keratinocytes can be independent of telomerase activation, involving an alternative pathway of telomere maintenance (ALT).
引用
收藏
页码:725 / 732
页数:8
相关论文
共 51 条
[1]   TELOMERE LENGTH PREDICTS REPLICATIVE CAPACITY OF HUMAN FIBROBLASTS [J].
ALLSOPP, RC ;
VAZIRI, H ;
PATTERSON, C ;
GOLDSTEIN, S ;
YOUNGLAI, EV ;
FUTCHER, AB ;
GREIDER, CW ;
HARLEY, CB .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (21) :10114-10118
[2]   Mice without telomerase: what can they teach us about human cancer? [J].
Artandi, SE ;
DePinho, RA .
NATURE MEDICINE, 2000, 6 (08) :852-855
[3]   Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice [J].
Artandi, SE ;
Chang, S ;
Lee, SL ;
Alson, S ;
Gottlieb, GJ ;
Chin, L ;
DePinho, RA .
NATURE, 2000, 406 (6796) :641-645
[4]  
BARTKOVA J, 1995, CANCER RES, V55, P949
[5]   Telomere shortening and tumor formation by mouse cells lacking telomerase RNA [J].
Blasco, MA ;
Lee, HW ;
Hande, MP ;
Samper, E ;
Lansdorp, PM ;
DePinho, RA ;
Greider, CW .
CELL, 1997, 91 (01) :25-34
[6]   Extension of life-span by introduction of telomerase into normal human cells [J].
Bodnar, AG ;
Ouellette, M ;
Frolkis, M ;
Holt, SE ;
Chiu, CP ;
Morin, GB ;
Harley, CB ;
Shay, JW ;
Lichtsteiner, S ;
Wright, WE .
SCIENCE, 1998, 279 (5349) :349-352
[7]  
BOND JA, 1994, ONCOGENE, V9, P1885
[8]  
Bova RJ, 1999, CLIN CANCER RES, V5, P2810
[9]   SV40-INDUCED IMMORTALIZATION OF HUMAN-CELLS [J].
BRYAN, TM ;
REDDEL, RR .
CRITICAL REVIEWS IN ONCOGENESIS, 1994, 5 (04) :331-357
[10]   Telomere dynamics and telomerase activity in in vitro immortalised human cells [J].
Bryan, TM ;
Reddel, RR .
EUROPEAN JOURNAL OF CANCER, 1997, 33 (05) :767-773