TSC2 regulates VEGF through mTOR-dependent and -independent pathways

被引:453
作者
Brugarolas, JB
Vazquez, F
Reddy, A
Sellers, WR
Kaelin, WG
机构
[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA
[3] Howard Hughes Med Inst, Boston, MA 02115 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1016/S1535-6108(03)00187-9
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Inactivation of the TSC2 tumor suppressor protein causes tuberous sclerosis complex (TSC), a disease characterized by highly vascular tumors. TSC2 has multiple functions including inhibition of mTOR (mammalian target of Rapamycin). We found that TSC2 regulates VEGF through mTOR-dependent and -independent pathways. TSC2 loss results in the accumulation of HIF-1alpha and increased expression of HIF-responsive genes including VEGF. Wild-type TSC2, but not a disease-associated TSC2 mutant, downregulates Hill Rapamycin normalizes HIF levels in TSC2(-/-) cells, indicating that TSC2 regulates HIF by inhibiting mTOR. In contrast, Rapamycin only partially downregulates VEGF in this setting, implying an mTOR-independent link between TSC2 loss and VEGF. This pathway may involve chromatin remodeling since the HDAC inhibitor Trichostatin A downregulates VEGF in TSC2(-/-) cells.
引用
收藏
页码:147 / 158
页数:12
相关论文
共 87 条
[11]   Norepinephrine induces vascular endothelial growth factor gene expression in brown adipocytes through a β-adrenoreceptor/cAMP/protein kinase A pathway involving Src but independently of Erk1/2 [J].
Fredriksson, JM ;
Lindquist, JM ;
Bronnikov, GE ;
Nedergaard, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (18) :13802-13811
[12]   DEFINITION OF 2 ANGIOGENIC PATHWAYS BY DISTINCT ALPHA(V) INTEGRINS [J].
FRIEDLANDER, M ;
BROOKS, PC ;
SHAFFER, RW ;
KINCAID, CM ;
VARNER, JA ;
CHERESH, DA .
SCIENCE, 1995, 270 (5241) :1500-1502
[13]   TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth [J].
Gao, XS ;
Pan, DJ .
GENES & DEVELOPMENT, 2001, 15 (11) :1383-1392
[14]   Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2 [J].
Garami, A ;
Zwartkruis, FJT ;
Nobukuni, T ;
Joaquin, M ;
Roccio, M ;
Stocker, H ;
Kozma, SC ;
Hafen, E ;
Bos, JL ;
Thomas, G .
MOLECULAR CELL, 2003, 11 (06) :1457-1466
[15]   Nitric oxide synthase inhibition attenuates the skeletal muscle VEGF mRNA response to exercise [J].
Gavin, TP ;
Spector, DA ;
Wagner, H ;
Breen, EC ;
Wagner, PD .
JOURNAL OF APPLIED PHYSIOLOGY, 2000, 88 (04) :1192-1198
[16]   Enhancement by histamine of vascular endothelial growth factor production in granulation tissue via H2 receptors [J].
Ghosh, AK ;
Hirasawa, N ;
Ohuchi, K .
BRITISH JOURNAL OF PHARMACOLOGY, 2001, 134 (07) :1419-1428
[17]   Regulation of translation initiation by FRAP/mTOR [J].
Gingras, AC ;
Raught, B ;
Sonenberg, N .
GENES & DEVELOPMENT, 2001, 15 (07) :807-826
[18]   Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation -: A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM) [J].
Goncharova, EA ;
Goncharov, DA ;
Eszterhas, A ;
Hunter, DS ;
Glassberg, MK ;
Yeung, RS ;
Walker, CL ;
Noonan, D ;
Kwiatkowski, DJ ;
Chou, MM ;
Panettieri, RA ;
Krymskaya, VP .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (34) :30958-30967
[19]   Mechanical stretch induces vascular permeability factor in human mesangial cells: Mechanisms of signal transduction [J].
Gruden, G ;
Thomas, S ;
Burt, D ;
Lane, S ;
Chusney, G ;
Sacks, S ;
Viberti, G .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (22) :12112-12116
[20]   Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor [J].
Guba, M ;
von Breitenbuch, P ;
Steinbauer, M ;
Koehl, G ;
Flegel, S ;
Hornung, M ;
Bruns, CJ ;
Zuelke, C ;
Farkas, S ;
Anthuber, M ;
Jauch, KW ;
Geissler, EK .
NATURE MEDICINE, 2002, 8 (02) :128-135