Sonic Hedgehog-induced Activation of the Gli1Promoter Is Mediated by GLI3

doi:10.1074/jbc.274.12.8143

Sonic Hedgehog-induced Activation of the Gli1Promoter Is Mediated by GLI3*

From the ^‡Laboratory of Molecular Genetics, Tsukuba Life Science Center, RIKEN, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan, the ^¶Division of Neurobiology, Department of Neuroscience, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, and ^§CREST, Japan Science and Technology

Abstract

Drosophila transcription factorcubitus interruptus (Ci) and its co-activator CRE (cAMP response element)-binding protein (CBP) activate a group of target genes on the anterior-posterior border in response to hedgehog protein (Hh) signaling. In the anterior region, in contrast, the carboxyl-truncated form of Ci generated by protein processing represses Hh expression. In vertebrates, three Ci-related transcription factors (glioblastoma gene products (GLIs) 1, 2, and 3) were identified, but their functional difference in Hh signal transduction is unknown. Here, we report distinct roles for GLI1 and GLI3 in Sonic hedgehog (Shh) signaling. GLI3 containing both repression and activation domains acts both as an activator and a repressor, as does Ci, whereas GLI1 contains only the activation domain. Consistent with this, GLI3, but not GLI1, is processed to generate the repressor form. Transcriptional co-activator CBP binds to GLI3, but not to GLI1. Thetrans-activating capacity of GLI3 is positively and negatively regulated by Shh and cAMP-dependent protein kinase, respectively, through a specific region of GLI3, which contains the CBP-binding domain and the phosphorylation sites of cAMP-dependent protein kinase. GLI3 directly binds to theGli1 promoter and induces Gli1 transcription in response to Shh. Thus, GLI3 may act as a mediator of Shh signaling in the activation of the target gene Gli1.

Footnotes

↵* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵‖ To whom correspondence should be addressed. Tel.: 81-298-36-9031; Fax: 81-298-36-9030; E-mail:sishii{at}rtc.riken.go.jp.
↵2 H. Park and A. L. Joyner, manuscript in preparation.
Abbreviations:

CBP

CRE (cAMP response element)-binding protein

Ci

cubitus interruptusgene product

GLI

glioblastoma gene product

Hh

hedgehog protein

PKA

cAMP-dependent protein kinase

Shh

Sonic hedgehog gene product

A-P

anterior-posterior

RTS

Rubinstein-Taybi syndrome

GCPS

Greig cephalopolysyndactyly syndrome

PHS

Pallister-Hall syndrome

PCR

polymerase chain reaction

MNS

multipotential neural stem

CAT

chloramphenicol acetyltransferase

CMV

cytomegalovirus

Shh

Sonic hedgehog
- Received July 27, 1998.
- Revision received December 18, 1998.
The American Society for Biochemistry and Molecular Biology, Inc.