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Negative regulation of beta4 integrin transcription by homeodomain-interacting protein kinase 2 and p53 impairs tumor progression.
- Source :
-
Cancer research [Cancer Res] 2009 Jul 15; Vol. 69 (14), pp. 5978-86. Date of Electronic Publication: 2009 Jun 30. - Publication Year :
- 2009
-
Abstract
- Increased expression of alpha(6)beta(4) integrin in several epithelial cancers promotes tumor progression; however, the mechanism underlying its transcriptional regulation remains unclear. Here, we show that depletion of homeodomain-interacting protein kinase 2 (HIPK2) activates beta(4) transcription that results in a strong increase of beta(4)-dependent mitogen-activated protein kinase and Akt phosphorylation, anchorage-independent growth, and invasion. In contrast, stabilization of HIPK2 represses beta(4) expression in wild-type p53 (wtp53)-expressing cells but not in p53-null cells or cells expressing mutant p53, indicating that HIPK2 requires a wtp53 to inhibit beta(4) transcription. Consistent with our in vitro findings, a strong correlation between beta(4) overexpression and HIPK2 inactivation by cytoplasmic relocalization was observed in wtp53-expressing human breast carcinomas. Under loss of function of HIPK2 or p53, the p53 family members TAp63 and TAp73 strongly activate beta(4) transcription. These data, by revealing that beta(4) expression is transcriptionally repressed in tumors by HIPK2 and p53 to impair beta(4)-dependent tumor progression, suggest that loss of p53 function favors the formation of coactivator complex with the TA members of the p53 family to allow beta(4) transcription.
- Subjects :
- Blotting, Western
Breast Neoplasms genetics
Breast Neoplasms metabolism
Breast Neoplasms pathology
Carrier Proteins genetics
Cell Line, Tumor
Cell Proliferation
Cytoplasm metabolism
Disease Progression
Female
Gene Expression Regulation, Neoplastic
HCT116 Cells
HT29 Cells
Histone Acetyltransferases metabolism
Humans
Immunohistochemistry
Integrin beta4 genetics
Mitogen-Activated Protein Kinases metabolism
Mutation
Neoplasms genetics
Neoplasms metabolism
Phosphorylation
Protein Serine-Threonine Kinases genetics
Proto-Oncogene Proteins c-akt metabolism
Reverse Transcriptase Polymerase Chain Reaction
Transcription, Genetic
Tumor Suppressor Protein p53 genetics
p300-CBP Transcription Factors metabolism
Carrier Proteins metabolism
Integrin beta4 metabolism
Neoplasms pathology
Protein Serine-Threonine Kinases metabolism
Tumor Suppressor Protein p53 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 69
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 19567674
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-09-0244