Histone deacetylase and Cullin3-RENKCTD11 ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation

被引：287

作者：

Canettieri, Gianluca ^{[1
]}

Di Marcotullio, Lucia ^{[1
]}

Greco, Azzura ^{[1
]}

Coni, Sonia ^{[1
]}

Antonucci, Laura ^{[1
]}

Infante, Paola ^{[1
]}

Pietrosanti, Laura ^{[1
]}

De Smaele, Enrico ^{[1
]}

Ferretti, Elisabetta ^{[1
]}

Miele, Evelina ^{[1
]}

Pelloni, Marianna ^{[1
]}

De Simone, Giuseppina ^{[5
]}

Pedone, Emilia Maria ^{[5
]}

Gallinari, Paola ^{[3
]}

Giorgi, Alessandra ^{[2
]}

Steinkuehler, Christian ^{[3
]}

Vitagliano, Luigi ^{[5
]}

Pedone, Carlo ^{[5
]}

Schinina, M. Eugenia ^{[2
]}

Screpanti, Isabella ^{[1
]}

Gulino, Alberto ^{[1
,4
]}

机构：

[1] Univ Roma La Sapienza, Dept Expt Med, I-00161 Rome, Italy

[2] Univ Roma La Sapienza, Dept Biochem Sci, I-00161 Rome, Italy

[3] IRBM, Merck Res Labs Rome, I-00040 Pomezia, Italy

[4] Neuromed Inst, I-86077 Pozzilli, Italy

[5] CNR, Inst Biostruct & Bioimaging, I-80134 Naples, Italy

来源：

NATURE CELL BIOLOGY | 2010年 / 12卷 / 02期

关键词：

GENE-EXPRESSION; MEDULLOBLASTOMA; PROLIFERATION; ACTIVATION; TRANSCRIPTION; SUPPRESSOR; NEUROGENESIS; DEGRADATION; RENKCTD11; NEURONS;

D O I：

10.1038/ncb2013

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Hedgehog signalling is crucial for development and is deregulated in several tumours, including medulloblastoma. Regulation of the transcriptional activity of Gli (glioma-associated oncogene) proteins, effectors of the Hedgehog pathway, is poorly understood. We show here that Gli1 and Gli2 are acetylated proteins and that their HDAC-mediated deacetylation promotes transcriptional activation and sustains a positive autoregulatory loop through Hedgehog-induced upregulation of HDAC1. This mechanism is turned off by HDAC1 degradation through an E3 ubiquitin ligase complex formed by Cullin3 and REN, a Gli antagonist lost in human medulloblastoma. Whereas high HDAC1 and low REN expression in neural progenitors and medulloblastomas correlates with active Hedgehog signalling, loss of HDAC activity suppresses Hedgehog-dependent growth of neural progenitors and tumour cells. Consistent with this, abrogation of Gli1 acetylation enhances cellular proliferation and transformation. These data identify an integrated HDAC-and ubiquitin-mediated circuitry, where acetylation of Gli proteins functions as an unexpected key transcriptional checkpoint of Hedgehog signalling.

引用

页码：132 / U91

页数：21

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