Negative regulation of beta4 integrin transcription by homeodomain-interacting protein kinase 2 and p53 impairs tumor progression.

Cancer Res 2009 Jul 30;69(14):5978-86. Epub 2009 Jun 30.

Molecular Oncogenesis Laboratory, Department of Experimental Oncology, Regina Elena Cancer Institute, Rome, Italy.

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.

Download full-text PDF

Source
http://cancerres.aacrjournals.org/cgi/doi/10.1158/0008-5472.
Publisher Site
http://dx.doi.org/10.1158/0008-5472.CAN-09-0244DOI Listing
July 2009

Publication Analysis

Top Keywords

beta4 transcription
16
protein kinase
12
tumor progression
12
hipk2 p53
8
p53 family
8
beta4 expression
8
p53
8
homeodomain-interacting protein
8
beta4
8
hipk2
6
transcription
5
vitro findings
4
consistent vitro
4
findings strong
4
cytoplasmic relocalization
4
inhibit beta4
4
transcription consistent
4
inactivation cytoplasmic
4
wtp53 inhibit
4
correlation beta4
4

Similar Publications