Identification of a family of cAMP response element-binding protein coactivators by genome-scale functional analysis in mammalian cells

Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12147-52. doi: 10.1073/pnas.1932773100.

Vadim Iourgenko ¹, Wenjun Zhang, Craig Mickanin, Ira Daly, Can Jiang, Jonathan M Hexham, Anthony P Orth, Loren Miraglia, Jodi Meltzer, Dan Garza, Gung-Wei Chirn, Elizabeth McWhinnie, Dalia Cohen, Joanne Skelton, Robert Terry, Yang Yu, Dale Bodian, Frank P Buxton, Jian Zhu, Chuanzheng Song, Mark A Labow

Affiliations

Affiliation

1 Department of Functional Genomics, Novartis Institute for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.

PMID: 14506290 DOI: 10.1073/pnas.1932773100

Abstract

This report describes an unbiased method for systematically determining gene function in mammalian cells. A total of 20,704 predicted human full-length cDNAs were tested for induction of the IL-8 promoter. A number of genes, including those for cytokines, receptors, adapters, kinases, and transcription factors, were identified that induced the IL-8 promoter through known regulatory sites. Proteins that acted through a cooperative interaction between an AP-1 and an unrecognized cAMP response element (CRE)-like site were also identified. A protein, termed transducer of regulated cAMP response element-binding protein (CREB) (TORC1), was identified that activated expression through the variant CRE and consensus CRE sites. TORC1 potently induced known CREB1 target genes, bound CREB1, and activated expression through a potent transcription activation domain. A functional Drosophila TORC gene was also identified. Thus, TORCs represent a family of highly conserved CREB coactivators that may control the potency and specificity of CRE-mediated responses.

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