Activation of the p21 Pathway of Growth Arrest and Apoptosis by the β4 Integrin Cytoplasmic Domain

doi:10.1074/jbc.270.39.22673

Activation of the p21 Pathway of Growth Arrest and Apoptosis by the β₄ Integrin Cytoplasmic Domain (*)

From the Laboratory of Cancer Biology, Deaconess Hospital and Harvard Medical School, Boston, Massachusetts 02115

^§ Recipient an American Cancer Society faculty research award. To whom correspondence should be addressed:
Laboratory of Cancer Biology, Deaconess Hospital, Harvard Medical School, 50 Binney St., Boston, MA 02115.
Tel.: 617-732-9874; Fax: 617-738-9188; mercurio{at}mbcrr.harvard.edu

Abstract

The integrin αβ, a receptor for members of the laminin family of basement membrane components, contributes to the function of epithelial cells and their oncogenically transformed derivatives. In our efforts to study αβ-mediated functions in more detail and to assess the contribution of the β cytoplasmic domain in such functions, we identified a rectal carcinoma cell line that lacks expression of the β integrin subunit. This cell line, termed RKO, expresses αβ but not αβ, and it interacts with laminin-1 less avidly than similar cell lines that express αβ. We expressed a full-length β cDNA, as well as a mutant cDNA that lacks the β cytoplasmic domain, in RKO cells and isolated stable subclones of these transfectants. In this study, we report that subclones that expressed the full-length β cDNA in association with endogenous α6 exhibited partial G arrest and apoptosis, properties that were not evident in RKO cells transfected with either the cytoplasmic domain mutant or the expression vector alone. In an effort to define a mechanism for these observed changes in growth, we observed that expression of the αβ integrin induced expression of the p21 (WAF1; CiP1) protein, an inhibitor of cyclin-dependent kinases. These data suggest that the β integrin cytoplasmic domain is linked to a signaling pathway involved in cell cycle regulation in the β transfected RKO cells.

Footnotes

↵* This work was supported by National Institutes of Health Grant CA44704. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

FCS

fetal calf serum

EHS

Englebreth-Holm-Swarm

PBS

phosphate-buffered saline

FACS

fluorescence-activated cell sorting

mAb

monoclonal antibody.
↵²M. M. Lotz and A. M. Mercurio, unpublished observation.
↵³W. G. Carter, unpublished observation.
- Received May 26, 1995.
- Revision received July 18, 1995.