Insensitivity to growth inhibition by TGF-beta1 correlates with a lack of inhibition of the CDK2 activity in prostate carcinoma cells.
TGF-beta is a potent growth inhibitor of epithelial cells. However, many transformed cells have lost their sensitivity to this growth inhibitory effect. The molecular mechanism of such insensitivity is not yet understood. Here, we have studied the TGF-beta1 effect on normal human prostate and carcinoma cells. Our results showed that normal cells were sensitive to growth inhibition, whereas tumor cells were not or only minimally inhibited regardless of the concentration of TGF-beta1 (20 to 80 pM) or time of exposure (1-5 days). p21WAF1/Cip1/Sdi1 and p15INK4B but not p27KIP1 were detectable by Western blotting in normal and tumor cells. TGF-beta1 treatment increased the association of p21WAF1/Cip1/Sdi1 with the Cdk2/cyclin E complex in both normal and prostate tumor cells. However, there was no increase in the association of p15INK4B nor p27Kip1 with the Cdk/cyclin complexes. In normal cells, the increase in the association of p21WAF1/Cip1/Sdi1. With the Cdk2/cyclin E complex resulted in inhibition of the Cdk2 activity. In contrast, although there was an increase in the association of p21WAF1/Cip1/Sdi1 with the Cdk2/cyclin E complex in tumor cells, there was no inhibition of the Cdk2 activity. These results indicate that a lack of inhibition of the Cdk2 activity correlates with insensitivity to TGF-beta1 in prostate tumor cells.
Cipriano
S C
SC
Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Chen
Y Q
YQ
D042846:CDC2-CDC28 Kinases; D002352:Carrier Proteins / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004794:Enzyme Repression; D004847:Epithelial Cells; D015972:Gene Expression Regulation, Neoplastic; D006131:Growth Inhibitors / Q000502:physiology*; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011467:Prostate / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D025521:Tumor Suppressor Proteins
C493956:CDKN1A protein, human; C493966:CDKN2B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006131:Growth Inhibitors; D008869:Microtubule-Associated Proteins; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases