Suppression of tumorigenicity by the wild-type tuberous sclerosis 2 (Tsc2) gene and its C-terminal region

被引:108
作者
Jin, F
Wienecke, R
Xiao, GH
Maize, JC
DeClue, JE
Yeung, RS
机构
[1] FOX CHASE CANC CTR,DIV MED SCI,PHILADELPHIA,PA 19111
[2] NCI,CELLULAR ONCOL LAB,BETHESDA,MD 20892
关键词
rat; renal carcinoma; hereditary cancer; inducible expression;
D O I
10.1073/pnas.93.17.9154
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
The Tsc2 gene, which is mutationally inactivated in the germ line of some families with tuberous sclerosis, encodes a large, membrane-associated GTPase activating protein (GAP) designated tuberin. Studies of the the Eker rat model of hereditary cancer strongly support the role of Tsc2 as a tumor suppressor gene. In this study, the biological activity of tuberin was assessed by expressing the wild-type Tsc2 gene in tumor cell lines lacking functional tuberin and also in rat fibroblasts with normal levels of endogenous tuberin. The colony forming efficiency of Eker fat-derived renal carcinoma cells was significantly reduced following reintroduction of wild-type Tsc2. Tumor cells expressing the transfected Tsc2 gene became more anchorage-dependent and lost their ability to form tumors in severe combined immunodeficient mice. At the cellular level, restoration of tuberin expression caused morphological changes characterized by enlargement of the cells and increased contact inhibition, As with the full-length Tsc2 gene, a clone encoding only the C terminus of tuberin (amino acids 1049-1809, including the GAP domain) was capable of reducing both colony formation and in vivo tumorigenicity when transfected into the Eker rat tumor cells, In normal Rat1 fibroblasts, conditional over-expression of tuberin also suppressed colony formation and cell growth in vitro, These results provide direct experimental evidence for the tumor suppressor function of Tsc2 and suggest that the tuberin C terminus plays an important role in this activity.
引用
收藏
页码:9154 / 9159
页数:6
相关论文
共 27 条
[1]   ABERRANT REGULATION OF RAS PROTEINS IN MALIGNANT-TUMOR CELLS FROM TYPE-1 NEUROFIBROMATOSIS PATIENTS [J].
BASU, TN ;
GUTMANN, DH ;
FLETCHER, JA ;
GLOVER, TW ;
COLLINS, FS ;
DOWNWARD, J .
NATURE, 1992, 356 (6371) :713-715
[2]   ABNORMAL REGULATION OF MAMMALIAN P21(RAS) CONTRIBUTES TO MALIGNANT-TUMOR GROWTH IN VONRECKLINGHAUSEN (TYPE-1) NEUROFIBROMATOSIS [J].
DECLUE, JE ;
PAPAGEORGE, AG ;
FLETCHER, JA ;
DIEHL, SR ;
RATNER, N ;
VASS, WC ;
LOWY, DR .
CELL, 1992, 69 (02) :265-273
[3]  
European Chromosome 16 Tuberous Sclerosis C., 1993, CELL, V75, P1305
[4]   A GENETIC MODEL FOR COLORECTAL TUMORIGENESIS [J].
FEARON, ER ;
VOGELSTEIN, B .
CELL, 1990, 61 (05) :759-767
[5]  
GEIST RT, 1995, CELL GROWTH DIFFER, V6, P1477
[6]  
Gomez M.R., 1988, TUBEROUS SCLEROSIS, VSecond
[7]   LOSS OF HETEROZYGOSITY ON CHROMOSOME 16P13.3 IN HAMARTOMAS FROM TUBEROUS SCLEROSIS PATIENTS [J].
GREEN, AJ ;
SMITH, M ;
YATES, JRW .
NATURE GENETICS, 1994, 6 (02) :193-196
[8]   SPONTANEOUS AND RADIATION-INDUCED RENAL TUMORS IN THE EKER RAT MODEL OF DOMINANTLY INHERITED CANCER [J].
HINO, O ;
KLEINSZANTO, AJP ;
FREED, JJ ;
TESTA, JR ;
BROWN, DQ ;
VILENSKY, M ;
YEUNG, RS ;
TARTOF, KD ;
KNUDSON, AG .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (01) :327-331
[9]   SUPPRESSION OF THE NEOPLASTIC PHENOTYPE BY REPLACEMENT OF THE RB GENE IN HUMAN CANCER-CELLS [J].
HUANG, HJS ;
YEE, JK ;
SHEW, JY ;
CHEN, PL ;
BOOKSTEIN, R ;
FRIEDMANN, T ;
LEE, EYHP ;
LEE, WH .
SCIENCE, 1988, 242 (4885) :1563-1566
[10]   NEUROFIBROMIN CAN INHIBIT RAS-DEPENDENT GROWTH BY A MECHANISM INDEPENDENT OF ITS GTPASE-ACCELERATING FUNCTION [J].
JOHNSON, MR ;
DECLUE, JE ;
FELZMANN, S ;
VASS, WC ;
XU, GF ;
WHITE, R ;
LOWY, DR .
MOLECULAR AND CELLULAR BIOLOGY, 1994, 14 (01) :641-645