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J. Biol. Chem., Vol. 282, Issue 42, 30707-30717, October 19, 2007

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Lactogens Promote Beta Cell Survival through JAK2/STAT5 Activation and Bcl-X_L Upregulation^*

Yuichi Fujinaka¹, Karen Takane, Hiroko Yamashita, and Rupangi C. Vasavada²

From the Division of Endocrinology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 and the Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan

One of the goals in the treatment for diabetes is to enhance pancreatic beta cell function, proliferation, and survival. This study explores the role of lactogenic hormones, prolactin (PRL) and placental lactogen (PL), in beta cell survival. We have previously shown that transgenic mice expressing mouse placental lactogen-1 (mPL1) in beta cells under the rat insulin II promoter (RIP) are resistant to the diabetogenic and cytotoxic effects of streptozotocin (STZ) in vivo. The current study demonstrates that lactogens protect rat insulinoma (INS-1) cells and primary mouse beta cells against two distinct beta cell death inducers, STZ and dexamethasone (DEX), in vitro. Further, we identify the mechanism through which lactogens protect beta cells against DEX-induced death. The signaling pathway mediating this protective effect is the janus-activated-kinase-2/signal transducer and activator of transcription-5 (JAK2/STAT5) pathway. This is demonstrated in INS-1 cells and primary mouse beta cells using three separate approaches, pharmacological inhibitors, JAK2-specific siRNAs and a dominant-negative STAT5 mutant. Furthermore, lactogens specifically and significantly increase the anti-apoptotic protein Bcl-X_L in insulinoma cells and mouse islets. Bcl-X_L-specific siRNA significantly inhibits lactogen-mediated protection against DEX-induced beta cell death. We believe this is the first direct demonstration of lactogens mediating their protective effect through the JAK2/STAT5 pathway in the beta cell and through Bcl-X_L in any cell type.

Received for publication, March 27, 2007 , and in revised form, August 22, 2007.

^* This work was supported by Grant DK-072264 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: The University of Tokushima, Tokushima, Japan.

² To whom correspondence should be addressed: Division of Endocrinology, University of Pittsburgh, 200 Lothrop St. BST-E1140, Pittsburgh, PA 15261. Tel.: 412-648-3246; Fax: 412-648-3290; E-mail: vasavada{at}dom.pitt.edu.

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