Document Detail


Decreased growth inhibitory responses of squamous carcinoma cells to interferon-gamma involve failure to recruit cki proteins into cdk2 complexes.
MedLine Citation:
PMID:  11710944     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Interferon-gamma induces an irreversible growth arrest and squamous differentiation in normal human epidermal keratinocytes. We present for the first time a careful biochemical analysis of the cell-cycle-related events that occur during interferon-gamma treatment of normal human epidermal keratinocytes. The interferon-gamma-induced irreversible growth arrest state is characterized by inhibition of cyclin-dependent kinases, prevention of Rb and p130 (Rb2) phosphorylation, and increases in p27(Kip1), p16(Ink4a), and p130 proteins, together with a transient increase in p21(Waf1/Cip1). Cells derived from squamous cell carcinomas are less responsive to interferon-gamma and do not terminally differentiate. We exploited these differences in response to interferon-gamma in order to identify the particular molecular defects in cell cycle control that promote carcinogenesis in squamous epithelia. In several squamous cell carcinoma cell lines as well as in interferon-gamma-insensitive HaCaT cells, interferon gamma was unable to significantly induce levels of p130 and/or p16 protein. In addition, p21 association with cdk2 complexes was undetectable in either the absence or the presence of interferon-gamma and, unlike normal human epidermal keratinocytes, p27 association with cdk2 did not increase with interferon-gamma treatment. These multiple defects appear to be intrinsic to the mechanisms of cell cycle regulation rather than due to defects in the interferon-gamma signaling pathway, as induction of several interferon-gamma-responsive genes including Stat 1, IRF-1, and p21 itself was normal. Interestingly, exogenous expression of p21 protein in the squamous cell carcinoma cell lines by adenovirus carrying wildtype p53 or p21 cDNA cooperated with interferon-gamma to produce a greater inhibition of growth than either agent alone, even though p21 protein could barely be detected in cdk2 complexes. We conclude that squamous cell carcinoma cells have intrinsic defects in their ability to regulate cdk-cki complexes in response to differentiation signals.
Authors:
B L Harvat; A M Jetten
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of investigative dermatology     Volume:  117     ISSN:  0022-202X     ISO Abbreviation:  J. Invest. Dermatol.     Publication Date:  2001 Nov 
Date Detail:
Created Date:  2001-11-16     Completed Date:  2001-12-20     Revised Date:  2012-06-25    
Medline Journal Info:
Nlm Unique ID:  0426720     Medline TA:  J Invest Dermatol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1274-81     Citation Subset:  IM    
Affiliation:
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA. harva001@mc.duke.edu
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MeSH Terms
Descriptor/Qualifier:
CDC2-CDC28 Kinases*
Carcinoma, Squamous Cell / metabolism*,  pathology*
Carrier Proteins / metabolism
Cell Cycle Proteins / metabolism
Cell Division / drug effects
Cell Line
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinase Inhibitor p27
Cyclin-Dependent Kinases / antagonists & inhibitors*,  metabolism*
Cyclins / metabolism
Drug Resistance
Humans
Interferon-gamma / pharmacology*,  physiology
Multigene Family
Protein-Serine-Threonine Kinases / metabolism*
Retinoblastoma Protein / genetics,  physiology
Signal Transduction / physiology
Time Factors
Tumor Suppressor Protein p53 / pharmacology
Tumor Suppressor Proteins / metabolism
Grant Support
ID/Acronym/Agency:
1K22ES00343-01/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/CDKN1A protein, human; 0/Carrier Proteins; 0/Cell Cycle Proteins; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/Retinoblastoma Protein; 0/Tumor Suppressor Protein p53; 0/Tumor Suppressor Proteins; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 82115-62-6/Interferon-gamma; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.22/CDC2-CDC28 Kinases; EC 2.7.11.22/CDK2 protein, human; EC 2.7.11.22/Cyclin-Dependent Kinase 2; EC 2.7.11.22/Cyclin-Dependent Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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