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PMID:16489008

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Citation

Adolphe, C, Hetherington, R, Ellis, T and Wainwright, B (2006) Patched1 functions as a gatekeeper by promoting cell cycle progression. Cancer Res. 66:2081-8

Abstract

Mutations in the Hedgehog receptor, Patched 1 (Ptch1), have been linked to both familial and sporadic forms of basal cell carcinoma (BCC), leading to the hypothesis that loss of Ptch1 function is sufficient for tumor progression. By combining conditional knockout technology with the inducible activity of the Keratin6 promoter, we provide in vivo evidence that loss of Ptch1 function from the basal cell population of mouse skin is sufficient to induce rapid skin tumor formation, reminiscent of human BCC. Elimination of Ptch1 does not promote the nuclear translocation of beta-catenin and does not induce ectopic activation or expression of Notch pathway constituents. In the absence of Ptch1, however, a large proportion of basal cells exhibit nuclear accumulation of the cell cycle regulators cyclin D1 and B1. Collectively, our data suggest that Ptch1 likely functions as a tumor suppressor by inhibiting G1-S phase and G2-M phase cell cycle progression, and the rapid onset of tumor progression clearly indicates Ptch1 functions as a "gatekeeper." In addition, we note the high frequency and rapid onset of tumors in this mouse model makes it an ideal system for testing therapeutic strategies, such as Patched pathway inhibitors.

Links

PubMed Online version:10.1158/0008-5472.CAN-05-2146

Keywords

Animals; Carcinoma, Basal Cell/genetics; Carcinoma, Basal Cell/metabolism; Carcinoma, Basal Cell/pathology; Cell Cycle/physiology; Cell Nucleus/metabolism; Cell Transformation, Neoplastic/genetics; Cell Transformation, Neoplastic/metabolism; Cell Transformation, Neoplastic/pathology; Cyclin B/metabolism; Cyclin B1; Cyclin D1/metabolism; Hair Follicle/metabolism; Hair Follicle/pathology; Mice; Mice, Transgenic; Receptors, Cell Surface/biosynthesis; Receptors, Cell Surface/genetics; Receptors, Cell Surface/physiology; Receptors, Notch/metabolism; Skin/metabolism; Skin/pathology; Skin Neoplasms/genetics; Skin Neoplasms/metabolism; Skin Neoplasms/pathology; beta Catenin/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:CCNB1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:CCND1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GLI1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:17528)

Seeded From UniProt

complete

MOUSE:CTNB1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:17528)

Seeded From UniProt

complete

MOUSE:CTNB1

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:17528)

Seeded From UniProt

complete

MOUSE:PTC1

acts_upstream_of_or_within

GO:0008285: negative regulation of cell population proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2675356

P

Seeded From UniProt

complete

MOUSE:PTC1

acts_upstream_of_or_within

GO:0007346: regulation of mitotic cell cycle

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2675356

P

Seeded From UniProt

complete

MOUSE:PTC1

acts_upstream_of_or_within

GO:0032880: regulation of protein localization

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2675356

P

Seeded From UniProt

complete

MOUSE:GLI1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(EMAPA:17528)

Seeded From UniProt

complete

MOUSE:CTNB1

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(EMAPA:17528)

Seeded From UniProt

complete

MOUSE:CTNB1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(EMAPA:17528)

Seeded From UniProt

complete


See also

References

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