Gli2 is targeted for ubiquitination and degradation by β-TrCP ubiquitin ligase

被引:116
作者
Bhatia, Neehar
Thiyagarajan, Saravanan
Elcheva, Irina
Saleem, Mohammed
Dlugosz, Andrzej
Mukhtar, Hasan
Spiegelman, Vladimir S.
机构
[1] Univ Wisconsin, Sch Med, Dept Dermatol, Madison, WI 53706 USA
[2] Univ Michigan, Sch Med, Dept Dermatol, Ann Arbor, MI 48109 USA
[3] Univ Michigan, Sch Med, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA
关键词
D O I
10.1074/jbc.M513203200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The Hedgehog (Hh) signaling pathway plays a crucial role in embryogenesis and has been linked to the development of several human malignancies. The transcription factor Gli2 plays a key role in the transduction of Hh signals by modulating transcription of some Hh target genes, yet the mechanisms that control Gli2 protein expression are largely unknown. Here we report that beta-transducin repeat-containing protein (beta-TrCP) E3 ubiquitin ligase is required for Gli2 degradation. beta-TrCP2 directly binds wild type Gli2 and promotes its ubiquitination. Single amino acid substitution in Gli2 putative binding site inhibits its interaction with beta-TrCP2, its ubiquitination, and stabilizes the Gli2 protein. Stable Gli2 mutant is expressed in higher levels and is more potent in the activation of Gli-dependent transcription as compared with wild type Gli2. We also found that GLI2 protein is expressed highly in prostate cancer cell lines and primary tumors, whereas the level of GLI2 mRNA is not appreciably different in normal and neoplastic prostate. These data identify beta-TrCP2 as a pivotal regulator of Gli2 expression and point to an important role for post-translational modulation of GLI2 protein levels in Hh pathway-associated human prostate cancer.
引用
收藏
页码:19320 / 19326
页数:7
相关论文
共 41 条
[1]   Gli and hedgehog in cancer:: Tumours, embryos and stem cells [J].
Altaba, AR ;
Sánchez, P ;
Dahmane, N .
NATURE REVIEWS CANCER, 2002, 2 (05) :361-372
[2]  
Bai CB, 2002, DEVELOPMENT, V129, P4753
[3]   Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours [J].
Berman, DM ;
Karhadkar, SS ;
Maitra, A ;
de Oca, RM ;
Gerstenblith, MR ;
Briggs, K ;
Parker, AR ;
Shimada, Y ;
Eshleman, JR ;
Watkins, DN ;
Beachy, PA .
NATURE, 2003, 425 (6960) :846-851
[4]   Hedgehog: an unusual signal transducer [J].
Bijlsma, MF ;
Spek, CA ;
Peppelenbosch, MP .
BIOESSAYS, 2004, 26 (04) :387-394
[5]   The Hedgehog signaling network [J].
Cohen, MM .
AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2003, 123A (01) :5-28
[6]   Sonic hedgehog-induced activation of the Gli1 promoter is mediated by GLI3 [J].
Dai, P ;
Akimaru, H ;
Tanaka, Y ;
Maekawa, T ;
Nakafuku, M ;
Ishii, S .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (12) :8143-8152
[7]  
DasGupta R, 1999, DEVELOPMENT, V126, P4557
[8]   SCF and cullin/RING H2-based ubiquitin ligases [J].
Deshaies, RJ .
ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, 1999, 15 :435-467
[9]   Hedgehog signalling in cancer formation and maintenance [J].
di Magliano, MP ;
Hebrok, M .
NATURE REVIEWS CANCER, 2003, 3 (12) :903-911
[10]  
Ding Q, 1998, DEVELOPMENT, V125, P2533