Frequent and early loss of the EGR1 corepressor NAB2 in human prostate carcinoma

Abdulkadir, Sarki A.; Carbone, Joseph M.; Naughton, Cathy K.; Humphrey, Peter A.; Catàlona, William J.; Milbrandt, Jeffrey

doi:10.1053/hupa.2001.27102

Cited by 56 publications

(49 citation statements)

References 13 publications

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“…NAB1 and NAB2 both repress EGR activation of several promoters (3,(22)(23)(24)(25)(26). Interestingly, although EGR1 is overexpressed in prostate cancer (5, 6), NAB2 expression is reduced in a majority of prostate cancer samples (27). This observation is consistent with the idea that derepression of EGR1 activity is a progression factor in prostate cancer.…”

Section: Appendicessupporting

confidence: 79%

Regulation of Egr1 Target Genes by the NuRD Chromatin Remodeling Complex

Svaren¹

2006

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY) SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTPrevious work had shown that the EGR1 transactivator is overexpressed in prostate cancer, while expression of its corepressor, NAB2, is reduced. Based on our recent characterization of an interaction between NAB2 and the NuRD (Nucleosome remodeling and disruption) chromatin remodeling complex, we have determined if loss of NAB2 expression results in loss of NuRD targeting to EGR1 target genes. In progress thus far, we have shown that repression of some NAB-regulated target genes in prostate cancer cells requires the NuRD chromatin remodeling complex. We have developed novel chromatin immunoprecipitation assays for the NuRD complex in prostate cells to demonstrate the colocalization of the NuRD complex on EGR1-regulated endogenous target genes. In addition, we have shown that recruitment of the NuRD complex to EGR1 target genes is dependent on NAB2. Finally, NuRD-dependent repression of NAB-regulated repression is sensitive to histone deacetylase inhibitors. These results provide the first functional description of one of the major HDAC-containing chromatin remodeling complexes in prostate cancer cells, and elucidate molecular consequences of loss of NAB2 corepressor function in prostate carcinogenesis by analyzing the mechanism of NAB2 corepressor function.

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Section: Appendicessupporting

confidence: 79%

Regulation of Egr1 Target Genes by the NuRD Chromatin Remodeling Complex

Svaren¹

2006

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“…EGR-1 overexpression is correlated with the loss of its co-repressor NAB2 in primary prostate carcinoma causing elevated EGR-1 transcriptional activity (Abdulkadir et al, 2001a). Egr-1 À/À TRAMP mice showed significant delay in prostate tumor formation compared with Egr-1 þ / þ TRAMP mice, suggesting that the loss of EGR-1 failed to prevent tumor initiation, but delayed the progression of tumors (Abdulkadir et al, 2001b).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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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.

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“…This tissue-specific oncogenic effect of EGR1 could be partially explained by frequent loss of its downstream genes, p53 and PTEN (17), and natural inhibitor, NAB2 (40), in prostate cancer and its capability to induce the expression of tumor-promoting growth factors. Indeed, E2F1, NF-nB, and EGR1 have been found to be overexpressed in prostate cancer concurrently and play critical roles in proliferation, survival, and metastasis (18,19,21,(41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

E2F1 Induces Tumor Cell Survival via Nuclear Factor-κB–Dependent Induction of EGR1 Transcription in Prostate Cancer Cells

et al. 2009

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Transcription factor E2F1 has been implicated in both apoptosis-promoting and apoptosis-suppressing effects. However, factors that mediate its antiapoptotic effects are still not identified. Using prostate tumor-derived cell lines, we showed here that E2F1 activated the expression of transcription factor EGR1 for promoting cell survival. E2F1 up-regulated the production of EGR1-induced growth factors, epidermal growth factor, platelet-derived growth factor, and insulin-like growth factor II, which in turn activated the phosphoinositide-3-kinase/Akt pathway to resist drug-induced apoptosis. Moreover, E2F1 directly induced the transcription of the Egr1 gene using the KB site located in its proximal promoter. E2F1 physically interacted with the RelA subunit of nuclear factor-KB and modulated its transactivity to fully activate EGR1 transcription. Together, these studies uncovered a novel mechanism for E2F1-induced suppression of apoptosis in prostate cancer.

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Frequent and early loss of the EGR1 corepressor NAB2 in human prostate carcinoma

Cited by 56 publications

References 13 publications

Regulation of Egr1 Target Genes by the NuRD Chromatin Remodeling Complex

Regulation of Egr1 Target Genes by the NuRD Chromatin Remodeling Complex

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

E2F1 Induces Tumor Cell Survival via Nuclear Factor-κB–Dependent Induction of EGR1 Transcription in Prostate Cancer Cells

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