Cellular factors may enable squamous carcinoma cells to overcome TGF beta-mediated repression of CDK2 activity.
Cell lines developed from head and neck squamous cell carcinomas exhibit variable responses to the negative regulatory effects of transforming growth factor beta (TGF beta) on cell growth. To analyse the effects of TGF beta on regulators of cell cycle progression, we characterised cell lines derived from head and neck squamous cell carcinoma (HNSCC) for their biological sensitivities to TGF beta, growth inhibition, then examined the effects of TGF beta treatment on the expression and activity of cyclin dependent kinases (CDKs) and inhibitors of these kinases. Western blot analysis of cell lysates from untreated or TGF beta-treated cultures showed no alterations in expression of CDK2, CDK4, CDK6 or cyclin E in cell lines which were either sensitive (HaCaT, HN6) or refractory (HN12, HN30) to the growth-inhibitory effects of TGF beta. However, treatment of cells with TGF beta resulted in a several fold increase in cellular levels of p21 (WAF1/Cip1), irrespective of biological response. Immune complex in vitro kinase assays demonstrated that the activity of CDK2 was inhibited by exposure to ligand in each case, confirming that a TGF beta signalling pathway which regulates kinase activity was intact in these cell lines. The data suggest that cellular factors expressed in HN12 and HN30 enable these cells to override TGF beta-mediated inhibition of CDK2 activity and allow cell cycle progression. This may represent an important mechanism which allows cells to evade growth arrest during malignant progression.
Lesaca
E E
EE
Laboratory of Cellular Development and Oncology, National Institute of Dental Research, Bethesda, MD 20892, USA.
Ensley
J F
JF
Yeudall
W A
WA
D042846:CDC2-CDC28 Kinases; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology; D002455:Cell Division; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000187:drug effects* / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases