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Open Access Research article

A novel mechanism of cell growth regulation by Cell Cycle and Apoptosis Regulatory Protein (CARP)-1

Yan Jiang156, Vineshkumar T Puliyappadamba2, Liyue Zhang56, Wenjuan Wu2, Anil Wali23, Michael B Yaffe4, Joseph A Fontana1 and Arun K Rishi2*

Author Affiliations

1 Department of Internal Medicine, Wayne State University and John D. Dingell VA Medical Center, Room B4325, 4646 John R, Detroit, MI 48201, USA

2 Karmanos Cancer Institute, Wayne State University and John D. Dingell VA Medical Center, Room B4325, 4646 John R, Detroit, MI 48201, USA

3 Department of Surgery, Wayne State University, and John D. Dingell VA Medical Center, Room B4245, 4646 John R, Detroit, MI 48201, USA

4 Biology Department, Massachusetts Institute of Technology, Cambridge, MA 02115, UK

5 Department of Biochemistry, University of Western Ontario Schulich School of Medicine and Dentistry, 4th Floor Victoria Research Labs, A4-130a 800 Commissioners Road East, London, ON N6C 2V5, UK

6 Department of Obstetrics & Gynecology, University of Western Ontario Schulich School of Medicine and Dentistry, 4th Floor Victoria Research Labs, A4-130a 800 Commissioners Road East, London, ON N6C 2V5, UK

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Journal of Molecular Signaling 2010, 5:7  doi:10.1186/1750-2187-5-7

Published: 1 July 2010

Abstract

Background

CARP-1/CCAR1, a perinuclear phospho-protein, regulates signaling by adriamycin, steroids, or growth factors. However, intracellular events that regulate CARP-1-dependent cell growth are not fully understood.

Results

Here we investigated whether CARP-1 is involved in signaling induced by the protein kinase A inhibitor H89. Treatments of human breast cancer cells with H89 resulted in apoptosis that involved enhanced CARP-1 threonine phosphorylation and expression. Depletion of CARP-1, on the other hand, abrogates apoptosis induced by H89. CARP-1 binds with signal transducer TAZ and over-expression of TAZ inhibits apoptosis by CARP-1. CARP-1 (651-759) interacts with a novel, N-terminal epitope of TAZ. H89 treatment stimulates threonine phosphorylation of CARP-1 (651-759), while substitution of threonine667 to alanine interferes with its binding with TAZ and apoptosis by H89. In addition, expression of wild type or CARP-1 (651-759) causes loss of c-myc expression due, in part, to suppression of c-myc transcription.

Conclusions

CARP-1 threonine667 regulates H89-dependent signaling by a novel pathway that involves modulation of CARP-1 interaction with TAZ and transcriptional down-regulation of c-myc.