Mechanism of telomerase repression during terminal differentiation of normal epithelial cells and squamous carcinoma lines.
Stratified squamous epithelial cells undergo an orderly process of cell cycle arrest following detachment from the basement membrane. The basal layer cells which adhere to the basement membrane express telomerase, which maintains the ends of chromosomes in this rapidly dividing population. Non-dividing suprabasal cells downregulate telomerase activity. However, the mechanisms regulating this inhibition are unknown. We examined the regulation of telomerase expression in anchorage-deprived normal human epidermal keratinocytes and squamous cell carcinoma lines. Anchorage-deprived cells underwent rapid loss of telomerase activity. Attachment loss was associated with increased ERK1 activity, G1 to S phase progression, and subsequent G2 arrest. Adhesion to collagen via specific integrin subunits inhibited ERK1 activity and telomerase repression. Loss of telomerase expression was associated with recruitment of an Rb/HDAC1 repressor complex to the -98 E2F site of the hTERT promoter. We propose a mechanism by which anchorage deprivation inhibits telomerase activity in stratified squamous epithelial cells and squamous cell carcinoma lines.
Crowe
David L
DL
Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA. dcrowe@usc.edu
Nguyen
Dan C
DC
Ohannessian
Arthur
A
D001665:Binding Sites; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology; D002453:Cell Cycle; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000494:pharmacology; D019925:Cyclin A / Q000032:analysis; D019926:Cyclin B / Q000032:analysis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*
D024141:Collagen Type IV; D019925:Cyclin A; D019926:Cyclin B; D004268:DNA-Binding Proteins; D005419:Flavonoids; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D019098:Telomerase; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one