EGR-1 forms a complex with YAP-1 and upregulates Bax expression in irradiated prostate carcinoma cells

M. Zagurovskaya, M. M. Shareef, A. Das, A. Reeves, S. Gupta, M. Sudol, M. T. Bedford, J. Prichard, M. Mohiuddin, M. M. Ahmed

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

In this study, we investigated the functional role of early growth response-1 (Egr1 gene) in the regulation of radiation-induced clonogenic inhibition and apoptosis in p53 wild-type and mutant prostate cancer cells 22Rv1 and DU145, respectively. 22Rv1 cells were more sensitive to irradiation compared with DU145 cells, and the sensitivity was enhanced by overexpression of EGR-1 in both cells. Dominant-negative EGR-1 mutant (dnEGR-1) or repressor of EGR-1, NGFIA binding protein 1 (NAB1), increased radioresistance of these cells. Significant activation of caspases 3 and 9 and Bcl2-associated X (Bax) with increased poly(ADP-ribose) polymerase (PARP) cleavage and cytochrome c release was observed in radiation-exposed EGR-1 overexpressing cells. Gel shift analysis and chloramphenicol acetyl transferase (CAT) reporter assays indicate that EGR-1 transactivates the promoter of the Bax gene. Interaction of EGR-1 and Yes kinase-associated protein 1 (YAP-1) through the WW domain of YAP-1 enhances the transcriptional activity of EGR-1 on the Bax promoter as shown by chromatin immunoprecipitation and reporter assays. Irradiation of PC3 cell xenografts that were treated with adenoviral EGR-1 showed significant regression in tumor volume. These findings establish the radiation-induced pro-apoptotic action of EGR-1, in a p53-independent manner, by directly transactivating Bax, and prove that alters the B-cell CLL/lymphoma 2 (Bcl-2)/Bax ratio as one of the mechanisms resulting in significant activation of caspases, leading to cell death through the novel interaction of EGR-1 with YAP-1.

Original languageEnglish (US)
Pages (from-to)1121-1131
Number of pages11
JournalOncogene
Volume28
Issue number8
DOIs
StatePublished - Feb 26 2009

Keywords

  • Bax
  • EGR-1
  • Prostate cancer
  • Radiation
  • YAP-1

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Zagurovskaya, M., Shareef, M. M., Das, A., Reeves, A., Gupta, S., Sudol, M., Bedford, M. T., Prichard, J., Mohiuddin, M., & Ahmed, M. M. (2009). EGR-1 forms a complex with YAP-1 and upregulates Bax expression in irradiated prostate carcinoma cells. Oncogene, 28(8), 1121-1131. https://doi.org/10.1038/onc.2008.461