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This version published online on July 3, 2002
Molecular Endocrinology, doi:10.1210/me.2002-0108
Molecular Endocrinology Vol. 0, No. 2002 200201081-
doi:10.1210/me.2002-0108
Copyright © 2002 by the Endocrine Society.
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Submitted on March 17, 2002
Accepted on June 5, 2002

CPAP is a novel Stat5-interacting cofactor that augments Stat5-mediated transcriptional activity

BENJAMIN PENG1, KATE D. SUTHERLAND1, ELEANOR Y. M. SUM1, MONILOLA OLAYIOYE1, SERGIO WITTLIN1, TANG K. TANG1, GEOFFREY J. LINDEMAN1, and JANE E. VISVADER1*

1 The Walter and Eliza Hall Institute of Medical Research & Rotary Bone Marrow Laboratories (B.P., K.D.S., E.Y.M.S., M.O., S.W., G.J.L., J.E.V.), PO Royal Melbourne Hospital, VIC 3050, Australia and Institute of Biomedical Sciences (T.K.T.), Academia Sinica, Taipei 115, Taiwan

* To whom correspondence should be addressed. E-mail: visvader{at}wehi.edu.au.

Stat5, a member of the signal transducer and activators of transcription (Stat) protein family, is a primary mediator of PRL signaling in the mammary gland. There are two distinct Stat5 genes, Stat5a and Stat5b. The Stat5a isoform has been demonstrated to have an essential role in mammary epithelial differentiation, while Stat5b is required for dimorphic sexual growth. To search for proteins that interact with the C-terminus of Stat5a, a highly divergent region amongst Stat family members, we performed a yeast two-hybrid screen of HBL100 and primary breast adenocarcinoma libraries. This led to the identification of a protein that had previously been isolated as a centrosomal protein termed CPAP. CPAP was shown to specifically interact with Stat5a and Stat5b but not with Stat1 or Stat3. Both the tyrosine phosphorylated and unphosphorylated forms of Stat5, as well as Stat5a/Stat5b heterodimers could associate with CPAP. CPAP was expressed in human breast cancer cell lines and the developing mammary gland as well as in other tissues. Indirect immunofluorescence and cellular fractionation studies revealed that CPAP was predominantly cytoplasmic, with low levels in the nucleus. Nuclear levels of CPAP increased substantially upon activation of the PRL pathway, most likely reflecting cotranslocation of this protein with activated Stat5. Furthermore, CPAP was found to augment Stat5-mediated transcription. Thus, we have identified CPAP as a novel coactivator of Stat5 proteins in the PRL (and probably other) pathways.
Key words: CPAP • cofactor • mammary • Stat5 Supporting agency: The Victorian Breast Cancer Research Consortium Inc




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