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J. Biol. Chem., Vol. 280, Issue 23, 22135-22145, June 10, 2005

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The Canonical Intrinsic Mitochondrial Death Pathway Has a Non-apoptotic Role in Signaling Lens Cell Differentiation^*

Gregory F. Weber and A. Sue Menko

From the Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

The mitochondrial cell death pathway is known for its role in signaling apoptosis. Here, we describe a novel function for the mitochondrial cell death pathway in signaling initiation of differentiation in the developing lens. Most remarkably, we induced lens cell differentiation by short-term exposure of lens epithelial cells to the apoptogen staurosporine. Activation of apoptosis-related pathways induced lens epithelial cells to express differentiation-specific markers and to undergo morphogenetic changes that led to formation of the lens-like structures known as lentoids. The fact that multiple stages of differentiation are expressed at a single stage of development in the embryonic lens made it possible to precisely determine the timing of expression of proteins associated with the apoptotic pathway. We discovered that there was high expression in the lens equatorial epithelium (the region of the lens in which differentiation is initiated) of pro-apoptotic molecules such as Bax and Bcl-x_S and release of cytochrome c from mitochondria. Furthermore, we found significant caspase-3-like activity in the equatorial epithelium, yet this activity was far lower than that associated with lens cell apoptosis. These apoptotic pathways are likely regulated by the concurrent expression of prosurvival molecules, including Bcl-2 and Bcl-x_L; phosphorylation of Bad; and high expression of inhibitor of apoptosis proteins chicken IAP1, IAP3, and survivin. This finding suggests that prosurvival pathways allow pro-apoptotic molecules to function as molecular switches in the differentiation process without tipping the balance toward apoptosis. We call this process apoptosis-related Bcl-2- and caspase-dependent (ABC) differentiation.

Received for publication, December 20, 2004 , and in revised form, March 23, 2005.

^* This work was supported in part by National Institutes of Health Grants EY10577, EY014798, and EY014258 (to A. S. M.). 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.

Supported by National Institutes of Health Training Grant ES007282.

To whom correspondence should be addressed: Dept. of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, 571 Jefferson Alumni Hall, 1020 Locust St., Philadelphia, PA 19107. Tel.: 215-503-2166; Fax: 215-923-3808; E-mail: sue.menko{at}jefferson.edu.

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