Activation of the p21 pathway of growth arrest and apoptosis by the beta 4 integrin cytoplasmic domain.
The integrin alpha 6 beta 4, 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 alpha 6 beta 4-mediated functions in more detail and to assess the contribution of the beta 4 cytoplasmic domain in such functions, we identified a rectal carcinoma cell line that lacks expression of the beta 4 integrin subunit. This cell line, termed RKO, expresses alpha 6 beta 1 but not alpha 6 beta 4, and it interacts with laminin-1 less avidly than similar cell lines that express alpha 6 beta 4. We expressed a full-length beta 4 cDNA, as well as a mutant cDNA that lacks the beta 4 cytoplasmic domain, in RKO cells and isolated stable subclones of these transfectants. In this study, we report that subclones that expressed the full-length beta 4 cDNA in association with endogenous alpha 6 exhibited partial G1 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 alpha 6 beta 4 integrin induced expression of the p21 (WAF1; CiP1) protein, an inhibitor of cyclin-dependent kinases. These data suggest that the beta 4 integrin cytoplasmic domain is linked to a signaling pathway involved in cell cycle regulation in the beta 4 transfected RKO cells.
Clarke
A S
AS
Laboratory of Cancer Biology, Deaconess Hospital, Boston, Massachusetts, USA.
Lotz
M M
MM
Chao
C
C
Mercurio
A M
AM
D015703:Antigens, CD / Q000096:biosynthesis / Q000378:metabolism*; D000954:Antigens, Surface / Q000378:metabolism; D017209:Apoptosis; D002453:Cell Cycle; D002455:Cell Division; D003001:Cloning, Molecular; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis*; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary; D004791:Enzyme Inhibitors / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D015151:Immunoblotting; D039161:Integrin alpha6beta4; D039663:Integrin beta4; D016023:Integrins / Q000378:metabolism; D016296:Mutagenesis; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D012004:Rectal Neoplasms; D017384:Sequence Deletion; D013379:Substrate Specificity; D014162:Transfection; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D000954:Antigens, Surface; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D039161:Integrin alpha6beta4; D039663:Integrin beta4; D016023:Integrins; D011994:Recombinant Proteins