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Molecular and Cellular Biology, September 2007, p. 6484-6496, Vol. 27, No. 18
0270-7306/07/$08.00+0     doi:10.1128/MCB.02409-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Identification of a WD40 Repeat-Containing Isoform of PHIP as a Novel Regulator of ß-Cell Growth and Survival

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada,¹ Children's Hospital of Philadelphia, Division of Endocrinology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania,² Children's Hospital, Harvard Medical School, Boston, Massachusetts³

Received 22 December 2006/ Returned for modification 6 February 2007/ Accepted 5 July 2007

The pleckstrin homology domain-interacting protein (PHIP) was originally identified as a 902-amino-acid (aa) protein that regulates insulin receptor-stimulated GLUT4 translocation in skeletal-muscle cells. Immunoblotting and immunohistological analyses of pancreatic ß-cells reveal prominent expression of a 206-kDa PHIP isoform restricted to the nucleus. Herein, we report the cloning of this larger, 1,821-aa isoform of PHIP (PHIP1), which represents a novel WD40 repeat-containing protein. We demonstrate that PHIP1 overexpression stimulates insulin-like growth factor 1-dependent and -independent proliferation of ß-cells, an event which correlates with transcriptional upregulation of the cyclin D2 promoter and the accumulation of cyclin D2 protein. RNA interference knockdown of PHIP1 in INS-1 cells abrogates insulin receptor substrate 2 (IRS2)-mediated DNA synthesis, providing for a specific role for PHIP1 in the enhancement of IRS2-dependent signaling responses leading to ß-cell growth. Finally, we provide evidence that PHIP1 overexpression blocks free fatty acid-induced apoptosis in INS-1 cells, which is accompanied by marked activation of phosphoprotein kinase B (PKB)/AKT and the concomitant inhibition of caspase-9 and caspase-3 cleavage. Our finding that the restorative effect of PHIP1 on ß-cell lipotoxicity can be attenuated by the overexpression of dominant-negative PKB suggests a key role for PKB in PHIP1-mediated cytoprotection. Taken together, these findings provide strong support for PHIP1 as a novel positive regulator of ß-cell function. We suggest that PHIP1 may be involved in the induction of long-term gene expression programs to promote ß-cell mitogenesis and survival.

Published ahead of print on 16 July 2007.