HOXA5-twist interaction alters p53 homeostasis in breast cancer cells.
The homeotic gene HOXA5 has been shown to play an important role in breast tumorigenesis. We have shown that loss of p53 correlated with loss of a developmentally regulated transcription factor, HOXA5, in primary breast cancer. Searching for potential protein interacting partners we found that HOXA5 binds to an anti-apoptotic protein, Twist. Furthermore, Twist-overexpressing MCF-7 cells displayed a deregulated p53 response to gamma-radiation and decreased regulation of downstream target genes. Using a p53-promoter-reporter system, we demonstrated that HOXA5 could partially restore the inhibitory effects of Twist on p53 target genes. These effects are likely mediated through both the transcriptional up-regulation of p53 and the protein-protein interaction between HOXA5 and Twist. Thus, the loss of HOXA5 expression could lead to the functional activation of Twist resulting in aberrant cell cycle regulation and promoting breast carcinogenesis.
Stasinopoulos
Ioannis A
IA
Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Mironchik
Yelena
Y
Raman
Ana
A
Wildes
Flonne
F
Winnard
Paul
P
Raman
Venu
V
D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005720:Gamma Rays; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051879:Twist-Related Protein 1; D020798:Two-Hybrid System Techniques
C489213:HOXA5 protein, human; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; C103173:TWIST1 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051879:Twist-Related Protein 1