title: Homeodomain protein DLX4 counteracts key transcriptional control mechanisms of the TGF-β cytostatic program and blocks the antiproliferative effect of TGF-β.
abstract: The antiproliferative activity of transforming growth factor-β (TGF-β) is essential for maintaining normal tissue homeostasis and is lost in many types of tumors. Gene responses that are central to the TGF-β cytostatic program include activation of the cyclin-dependent kinase inhibitors, p15(Ink4B) and p21(WAF1/Cip1), and repression of c-myc. These gene responses are tightly regulated by a repertoire of transcription factors that include Smad proteins and Sp1. The DLX4 homeobox patterning gene encodes a transcription factor that is absent from most normal adult tissues, but is expressed in a wide variety of malignancies, including lung, breast, prostate and ovarian cancers. In this study, we demonstrate that DLX4 blocks the antiproliferative effect of TGF-β. DLX4 inhibited TGF-β-mediated induction of p15(Ink4B) and p21(WAF1/Cip1) expression. DLX4 bound and prevented Smad4 from forming complexes with Smad2 and Smad3, but not with Sp1. However, DLX4 also bound and inhibited DNA-binding activity of Sp1. In addition, DLX4 induced expression of c-myc independently of TGF-β/Smad signaling. The ability of DLX4 to counteract key transcriptional control mechanisms of the TGF-β cytostatic program could explain, in part, the resistance of tumors to the antiproliferative effect of TGF-β.
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: B Q
authors.initials: BQ
authors.lastname: Trinh
authors.forename: N
authors.initials: N
authors.lastname: Barengo
authors.forename: H
authors.initials: H
authors.lastname: Naora
mesh_terms: D019485:Bone Morphogenetic Proteins / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D011401:Promoter Regions, Genetic; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D051901:Smad4 Protein / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; C105304:DLX4 protein, human; D018398:Homeodomain Proteins; C497796:SMAD4 protein, human; D051896:Smad Proteins, Receptor-Regulated; D051901:Smad4 Protein; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D016212:Transforming Growth Factor beta