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

Authors

Yan Jiang Department of Internal Medicine, Wayne State University and John D. Dingell VA Medical Center, Room B4325, 4646 John R, Detroit, MI 48201, USA 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 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
Vineshkumar T Puliyappadamba Karmanos Cancer Institute, Wayne State University and John D. Dingell VA Medical Center, Room B4325, 4646 John R, Detroit, MI 48201, USA
Liyue Zhang 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 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
Wenjuan Wu Karmanos Cancer Institute, Wayne State University and John D. Dingell VA Medical Center, Room B4325, 4646 John R, Detroit, MI 48201, USA
Anil Wali Karmanos Cancer Institute, Wayne State University and John D. Dingell VA Medical Center, Room B4325, 4646 John R, Detroit, MI 48201, USA Department of Surgery, Wayne State University, and John D. Dingell VA Medical Center, Room B4245, 4646 John R, Detroit, MI 48201, USA
Michael B Yaffe Biology Department, Massachusetts Institute of Technology, Cambridge, MA 02115, UK
Joseph A Fontana Department of Internal Medicine, Wayne State University and John D. Dingell VA Medical Center, Room B4325, 4646 John R, Detroit, MI 48201, USA
Arun K Rishi Karmanos Cancer Institute, Wayne State University and John D. Dingell VA Medical Center, Room B4325, 4646 John R, Detroit, MI 48201, USA

DOI:

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.

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Published

2010-07-01

Issue

Vol. 5 (2010)

Section

Research Articles

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