title: A novel transcription complex that selectively modulates apoptosis of breast cancer cells through regulation of FASTKD2.
abstract: We previously reported that expression of NRIF3 (nuclear receptor interacting factor-3) rapidly and selectively leads to apoptosis of breast cancer cells. DIF-1 (also known as interferon regulatory factor-2 binding protein 2 [IRF-2BP2]), the cellular target of NRIF3, was identified as a transcriptional repressor, and DIF-1 knockdown leads to apoptosis of breast cancer cells but not other cell types. Here, we identify IRF-2BP1 and EAP1 (enhanced at puberty 1) as important components of the DIF-1 complex mediating both complex stability and transcriptional repression. This interaction of DIF-1, IRF-2BP1, and EAP1 occurs through the conserved C4 zinc fingers of these proteins. Microarray studies were carried out in breast cancer cell lines engineered to conditionally and rapidly increase the levels of the death domain (DD1) region of NRIF3. The DIF-1 complex was found to repress FASTKD2, a putative proapoptotic gene, in breast cancer cells and to bind to the FASTKD2 gene by chromatin immunoprecipitation. FASTKD2 knockdown prevents apoptosis of breast cancer cells from NRIF3 expression or DIF-1 knockdown, while expression of FASTKD2 leads to apoptosis of both breast and nonbreast cancer cells. Thus, regulation of FASTKD2 by NRIF3 and the DIF-1 complex acts as a novel death switch that selectively modulates apoptosis in breast cancer.
authors: Department of Pharmacology, MSB 424, New York University School of Medicine, 550 First Ave, New York, NY 10016, USA.
authors: Kay T
authors: KT
authors: Yeung
authors: Sharmistha
authors: S
authors: Das
authors: Jin
authors: J
authors: Zhang
authors: Alejandro
authors: A
authors: Lomniczi
authors: Sergio R
authors: SR
authors: Ojeda
authors: Chong-Feng
authors: CF
authors: Xu
authors: Thomas A
authors: TA
authors: Neubert
authors: Herbert H
authors: HH
authors: Samuels
mesh_terms: D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins; D005260:Female; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D013058:Mass Spectrometry; D046228:Microarray Analysis; D051336:Mitochondrial Membranes / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D064249:Securin; D014157:Transcription Factors; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C475082:IRF2BP2 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D064249:Securin; D014157:Transcription Factors; C578002:pituitary tumor-transforming protein 1, human; C475081:IRF2BP1 protein, human; D044767:Ubiquitin-Protein Ligases; C532222:FASTKD2 protein, human; D017346:Protein Serine-Threonine Kinases