Cell anchorage regulates apoptosis through the retinoblastoma tumor suppressor/E2F pathway.
Epithelial cells are dependent upon adhesion to extracellular matrix for survival. We show that loss of beta1 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.
Day
M L
ML
Department of Surgery, Division of Urology, and the University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA. mday@umich.edu
Foster
R G
RG
Day
K C
KC
Zhao
X
X
Humphrey
P
P
Swanson
P
P
Postigo
A A
AA
Zhang
S H
SH
Dean
D C
DC
D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins; D002369:Castration; D002448:Cell Adhesion; D018797:Cell Cycle Proteins / Q000378:metabolism*; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050684:E2F Transcription Factors; D004847:Epithelial Cells; D005109:Extracellular Matrix / Q000378:metabolism; D006131:Growth Inhibitors / Q000378:metabolism*; D019012:Integrin beta1 / Q000378:metabolism; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism*; D011467:Prostate / Q000166:cytology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism*
D002352:Carrier Proteins; C534704:Ccng1 protein, rat; D018797:Cell Cycle Proteins; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D006131:Growth Inhibitors; D019012:Integrin beta1; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors