Sonic hedgehog opposes epithelial cell cycle arrest.
Stratified epithelium displays an equilibrium between proliferation and cell cycle arrest, a balance that is disrupted in basal cell carcinoma (BCC). Sonic hedgehog (Shh) pathway activation appears sufficient to induce BCC, however, the way it does so is unknown. Shh-induced epidermal hyperplasia is accompanied by continued cell proliferation in normally growth arrested suprabasal cells in vivo. Shh-expressing cells fail to exit S and G2/M phases in response to calcium-induced differentiation and also resist exhaustion of replicative growth capacity. In addition, Shh blocks p21(CIP1/WAF1)-induced growth arrest. These data indicate that Shh promotes neoplasia by opposing normal stimuli for epithelial cell cycle arrest.
Fan
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H
VA Palo Alto Health Care System, Palo Alto, California 94304, USA.
Khavari
P A
PA
D000818:Animals; D042846:CDC2-CDC28 Kinases; D002118:Calcium / Q000378:metabolism; D002280:Basal Cell Carcinoma / Q000473:pathology; D002453:Cell Cycle; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D004817:Epidermis / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D053823:Hedgehog Proteins; D006801:Humans; D006965:Hyperplasia; D015603:Keratinocytes / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism / Q000637:transplantation; D051379:Mice; D016513:Mice, SCID; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014161:Transduction, Genetic
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D053823:Hedgehog Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; C509239:SHH protein, human; D015534:Trans-Activators; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D002118:Calcium