|
rdf:type |
|
|
lifeskim:mentions |
|
|
pubmed:issue |
2
|
|
pubmed:dateCreated |
2004-1-5
|
|
pubmed:abstractText |
Basal cell carcinomas (BCCs) express high levels of the antiapoptotic proto-oncogene, bcl-2, and we have shown that bcl-2 contributes to the malignant phenotype in a transgenic mouse model. The basis of bcl-2 transcriptional regulation in keratinocytes is unknown. The sonic hedgehog (SHH) signaling pathway is frequently altered in BCCs. Mediators of shh signaling include the downstream transactivator, gli-1, and transrepressor, gli-3. Seven candidate gli binding sites were identified in the bcl-2 promoter. Cotransfection of increasing amounts of gli-1 in keratinoycytes resulted in a corresponding dose-dependent increase in bcl-2 promoter luciferase activity. Gli-1 was also able to up-regulate endogenous bcl-2. Gli-3 cotransfection resulted in no significant changes in bcl-2 promoter activity compared with control. Gli-3 has been demonstrated to be proteolytically processed into an N-terminal repressive form that can inhibit downstream transactivation by gli-1. Gli-3 mutants possessing only the N-terminal region or the C-terminal region were made and used in luciferase assays. The N terminus of gli-3 inhibited gli-1 transactivation of the bcl-2 promoter. Gel shift analysis and luciferase assays demonstrated that gli binding site 4 (-428 to -420), is important for gli transcriptional regulation. Skin samples from transgenic mice expressing an RU486 gli-1 transgene exhibited significantly higher levels of endogenous bcl-2 protein in epidermal keratinocytes as assessed by immunoblotting and immunohistochemistry. Together, these findings provide consistent evidence that gli proteins can transcriptionally regulate the bcl-2 promoter and that gli-3 can inhibit transactivation by gli-1. These studies further suggest that one consequence of the deregulation of shh signaling in BCC is the up-regulation of bcl-2.
|
|
pubmed:grant |
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/DNA, Complementary,
http://linkedlifedata.com/resource/pubmed/chemical/GLI1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Gli protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Hedgehog Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Kruppel-Like Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Luciferases,
http://linkedlifedata.com/resource/pubmed/chemical/Mifepristone,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-bcl-2,
http://linkedlifedata.com/resource/pubmed/chemical/SHH protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Jan
|
|
pubmed:issn |
0021-9258
|
|
pubmed:author |
|
|
pubmed:issnType |
Print
|
|
pubmed:day |
9
|
|
pubmed:volume |
279
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
1197-205
|
|
pubmed:dateRevised |
2008-11-21
|
|
pubmed:meshHeading |
pubmed-meshheading:14555646-3T3 Cells,
pubmed-meshheading:14555646-Animals,
pubmed-meshheading:14555646-Binding Sites,
pubmed-meshheading:14555646-Blotting, Western,
pubmed-meshheading:14555646-Cells, Cultured,
pubmed-meshheading:14555646-Coculture Techniques,
pubmed-meshheading:14555646-DNA, Complementary,
pubmed-meshheading:14555646-Dose-Response Relationship, Drug,
pubmed-meshheading:14555646-Exons,
pubmed-meshheading:14555646-Hedgehog Proteins,
pubmed-meshheading:14555646-Humans,
pubmed-meshheading:14555646-Immunoblotting,
pubmed-meshheading:14555646-Immunohistochemistry,
pubmed-meshheading:14555646-Keratinocytes,
pubmed-meshheading:14555646-Kruppel-Like Transcription Factors,
pubmed-meshheading:14555646-Luciferases,
pubmed-meshheading:14555646-Male,
pubmed-meshheading:14555646-Mice,
pubmed-meshheading:14555646-Mice, Transgenic,
pubmed-meshheading:14555646-Mifepristone,
pubmed-meshheading:14555646-Models, Genetic,
pubmed-meshheading:14555646-Promoter Regions, Genetic,
pubmed-meshheading:14555646-Protein Structure, Tertiary,
pubmed-meshheading:14555646-Proto-Oncogene Proteins c-bcl-2,
pubmed-meshheading:14555646-Signal Transduction,
pubmed-meshheading:14555646-Trans-Activators,
pubmed-meshheading:14555646-Transcription, Genetic,
pubmed-meshheading:14555646-Transcription Factors,
pubmed-meshheading:14555646-Transcriptional Activation,
pubmed-meshheading:14555646-Transfection,
pubmed-meshheading:14555646-Transgenes,
pubmed-meshheading:14555646-Up-Regulation
|
|
pubmed:year |
2004
|
|
pubmed:articleTitle |
Transcriptional regulation of bcl-2 mediated by the sonic hedgehog signaling pathway through gli-1.
|
|
pubmed:affiliation |
Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
|
|
pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
|
