Cell Anchorage Regulates Apoptosis through the Retinoblastoma Tumor Suppressor/E2F Pathway

doi:10.1074/jbc.272.13.8125

Cell Anchorage Regulates Apoptosis through the Retinoblastoma Tumor Suppressor/E2F Pathway*

From the ^‡ Department of Surgery, Division of Urology, and the University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, the
^‡‡ Department of Medicine and Cell Biology, Washington University School of Medicine, St. Louis, Missouri 63110, and the
** Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110

^¶To whom correspondence should be addressed:
University of Michigan, 1150 West Medical Center Dr., Rm. 5510 MSRBI, Ann Arbor, MI 48109-0680.
Tel.: 313-763-9968; Fax: 313-763-4151; E-mail: mday{at}umich.edu

Abstract

Epithelial cells are dependent upon adhesion to extracellular matrix for survival. We show that loss of β1 integrin receptor contact with extracellular matrix signals the inhibition of G₁ cyclin-dependent kinase activity. This loss of cyclin-dependent kinase activity leads to accumulation of the hypophosphorylated (active) form of the retinoblastoma tumor suppressor protein (Rb). We present evidence that in epithelial cells deprived of matrix contact, the growth suppression signal elicited by hypophosphorylated Rb opposes stimulatory signals from serum growth factors, leading to a cell cycle conflict that triggers apoptosis. This apoptotic pathway is modulated by Bcl-2 through a novel mechanism that regulates Rb phosphorylation. We present evidence that the Rb-dependent apoptotic pathway functions in vivo in the apoptosis of the prostate glandular epithelium following castration.

Footnotes

↵^∥ Supported by the American Lung Association.
↵^§ These authors contributed equally this work.
↵* This work was supported by National Institutes of Health Specialized Project of Research Excellence Grant CA69568, American Cancer Society Grant JRFA-531, and funds from the Blowitz Ridgeway Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

ECM

extracellular matrix

cdk

cyclin-dependent kinase

Rb

retinoblastoma tumor suppressor protein

TUNEL

TdT-mediated dUTP-biotin nick end labeling.
- Received December 24, 1996.
- Revision received January 21, 1997.