title: Inhibitor of differentiation 4 (ID4) acts as an inhibitor of ID-1, -2 and -3 and promotes basic helix loop helix (bHLH) E47 DNA binding and transcriptional activity.
abstract: The four known ID proteins (ID1-4, Inhibitor of Differentiation) share a homologous helix loop helix (HLH) domain and act as dominant negative regulators of basic-HLH transcription factors. ID proteins also interact with many non-bHLH proteins in complex networks. The expression of ID proteins is increasingly observed in many cancers. Whereas ID-1, ID-2 and ID-3, are generally considered as tumor promoters, ID4 on the contrary has emerged as a tumor suppressor. In this study we demonstrate that ID4 heterodimerizes with ID-1, -2 and -3 and promote bHLH DNA binding, essentially acting as an inhibitor of inhibitors of differentiation proteins. Interaction of ID4 was observed with ID1, ID2 and ID3 that was dependent on intact HLH domain of ID4. Interaction with bHLH protein E47 required almost 3 fold higher concentration of ID4 as compared to ID1. Furthermore, inhibition of E47 DNA binding by ID1 was restored by ID4 in an EMSA binding assay. ID4 and ID1 were also colocalized in prostate cancer cell line LNCaP. The alpha helix forming alanine stretch N-terminal, unique to HLH ID4 domain was required for optimum interaction. Ectopic expression of ID4 in DU145 prostate cancer line promoted E47 dependent expression of CDKNI p21. Thus counteracting the biological activities of ID-1, -2 and -3 by forming inactive heterodimers appears to be a novel mechanism of action of ID4. These results could have far reaching consequences in developing strategies to target ID proteins for cancer therapy and understanding biologically relevant ID-interactions.
authors.affiliation: Center for Cancer Research and Therapeutic Development, Clark Atlanta University, 223 James P. Brawley Dr. SW, Atlanta, GA, 30314, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Center for Cancer Research and Therapeutic Development, Clark Atlanta University, 223 James P. Brawley Dr. SW, Atlanta, GA, 30314, USA.
authors.forename: Swathi
authors.initials: S
authors.lastname: Chinaranagari
authors.affiliation: Center for Cancer Research and Therapeutic Development, Clark Atlanta University, 223 James P. Brawley Dr. SW, Atlanta, GA, 30314, USA. Electronic address: jchaudhary@cau.edu.
authors.forename: Jaideep
authors.initials: J
authors.lastname: Chaudhary
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051797:Inhibitor of Differentiation Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051796:Inhibitor of Differentiation Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051798:Inhibitor of Differentiation Protein 1; D051797:Inhibitor of Differentiation Protein 2; D051796:Inhibitor of Differentiation Proteins; D009363:Neoplasm Proteins; C497453:ID1 protein, human; C497450:ID2 protein, human; C490128:ID4 protein, human; C407909:TCF3 protein, human; C075640:ID3 protein, human
keywords: Cancer; DNA-Protein interaction; ID4; Protein–protein interaction; Tumor suppressor gene