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J. Biol. Chem., Vol. 282, Issue 33, 24471-24476, August 17, 2007

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The Cyclin-dependent Kinase Inhibitors p15^INK4B and p21^CIP1 Are Critical Regulators of Fibrillar Collagen-induced Tumor Cell Cycle Arrest^*

Steven J. Wall, Zhi-Duan Zhong, and Yves A. DeClerck^¶1

From the Division of Hematology-Oncology and Departments of Pediatrics and ^¶Biochemistry and Molecular Biology, University of Southern California and the Saban Research Institute of the Childrens Hospital Los Angeles, Los Angeles, California 90027 and AmCyte Inc., Santa Monica, California 90404

The extracellular matrix is a crucial component in determining cell fate. Fibrillar collagen in its native form inhibits cell proliferation, whereas in its monomeric form it stimulates proliferation. The observation of elevated levels of p27^KIP1 in cells plated in the presence of fibrillar collagen has led to the assumption that this kinase inhibitor was responsible for cell cycle arrest on fibrillar collagen. Here we provide evidence that p15^INK4b, rather than p27^KIP1, is the cyclin-dependent kinase inhibitor responsible for G₀/G₁ arrest of human melanoma cells grown on fibrillar collagen. Additionally, we demonstrate that fibrillar collagen can also arrest cells at the G₂ phase, which is mediated in part by p21^CIP1. Our data, in addition to identifying cyclin-dependent kinase inhibitors important in cell cycle arrest mediated by fibrillar collagen, demonstrate the complexity of cell cycle regulation and indicate that modulating a single cyclin-dependent kinase inhibitor does not disrupt cell proliferation in the presence of fibrillar collagen.

Received for publication, March 29, 2007 , and in revised form, June 6, 2007.

^* This work was supported by NCI, National Institutes of Health Grants R01 CA42919 and R01 CA98469. 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 To whom correspondence should be addressed: Childrens Hospital Los Angeles, 4650 Sunset Blvd., MailStop 54, Los Angeles, CA 90027. Tel.: 323-669-2150; Fax: 323-664-9455; E-mail: declerck{at}usc.edu.

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