Abstract
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.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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CDC2-CDC28 Kinases*
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Calcium / metabolism
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Carcinoma, Basal Cell / pathology
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Cell Cycle*
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Cell Differentiation
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Cell Division
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Cells, Cultured
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinases / metabolism
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Cyclins / genetics
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Cyclins / metabolism
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Enzyme Activation
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Epidermis / metabolism
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Epidermis / pathology
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Epidermis / transplantation
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Hedgehog Proteins
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Humans
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Hyperplasia
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Keratinocytes / cytology*
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Keratinocytes / enzymology
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Keratinocytes / metabolism
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Keratinocytes / transplantation
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Mice
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Mice, SCID
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Protein Serine-Threonine Kinases / metabolism
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Proteins / genetics
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Proteins / metabolism*
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Proto-Oncogene Proteins*
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Trans-Activators*
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Transduction, Genetic
Substances
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CDKN1A protein, human
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Cdkn1a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Hedgehog Proteins
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Proteins
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Proto-Oncogene Proteins
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SHH protein, human
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Trans-Activators
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Protein Serine-Threonine Kinases
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CDC2-CDC28 Kinases
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CDK2 protein, human
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CDK4 protein, human
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Cdk2 protein, mouse
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Cdk4 protein, mouse
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinases
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Calcium