CELL ANCHORAGE REGULATES APOPTOSIS THROUGH THE RETINOBLASTOMA TUMOR-SUPPRESSOR E2F PATHWAY

Epithelial cells are dependent upon adhesion to extracellular matrix f or survival. We show that loss of beta 1 integrin receptor contact wit h extracellular matrix signals the inhibition of G(1) cyclin-dependent kinase activity. This loss of cyclin-dependent kinase activity leads to accumulation of the hypophosphorylated (active) form of the retinob lastoma tumor suppressor protein (Rb). We present evidence that in epi thelial cells deprived of matrix contact, the growth suppression signa l elicited by hypophosphorylated Rb opposes stimulatory signals hom se rum growth factors, leading to a cell cycle conflict that triggers apo ptosis. This apoptotic pathway is modulated by Bcl-2 through a novel m echanism that regulates Rb phosphorylation. We present evidence that t he Rb-dependent apoptotic pathway functions in vivo in the apoptosis o f the prostate glandular epithelium following castration.