HOXA5 regulates hMLH1 expression in breast cancer cells.
Homeobox protein HOXA5 functions as a transcriptional factor for genes that are not only involved in segmentation identity but also in cell differentiation. Although HOXA5 has been shown to regulate the expression of the tumor-suppressor protein p53, its role in breast tumorigenesis is not well understood. Using yeast as a model system, we now demonstrate that overexpression of HOXA5 in yeast can be used to identify downstream target genes that are homologous in humans. One such identified gene was that of the mismatch repair pathway component MutL homolog 1. Analysis of the promoter region of the gene for human MutL homolog 1 (hMLH1) displayed several putative HOXA5-binding sites. In transient transfection experiments, the overexpression of HOXA5 transactivated the hMLH1 promoter-reporter construct. In addition, chromatin immunoprecipitation assay using a human breast cancer cell line MCF-7 demonstrated that HOXA5 binds to the hMLH1 promoter in vivo. Furthermore, we demonstrate that, in the presence of HOXA5, there is an increase in in vivo repair activity in MCF-7 cells. Taken together, our results indicate that HOXA5 is a transcriptional regulator of hMLH1 in breast cancer cells.
Duriseti
Sai
S
Department of Radiology, Johns Hopkins University School of Medicine, 340 Traylor Building, 720 Rutland Avenue, Baltimore, MD 21205, USA.
Winnard
Paul T
PT
Mironchik
Yelena
Y
Vesuna
Farhad
F
Raman
Ana
A
Raman
Venu
V
D048868:Adaptor Proteins, Signal Transducing; D001943:Breast Neoplasms / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000096:biosynthesis*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012441:Saccharomyces cerevisiae; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C489213:HOXA5 protein, human; D018398:Homeodomain Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D000070957:MutL Protein Homolog 1