The Kaposi's sarcoma-associated herpesvirus K-bZIP protein represses transforming growth factor beta signaling through interaction with CREB-binding protein.
Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is involved in the pathogenesis of KS, primary effusion lymphoma, and multicentric Castleman's disease. K-bZIP, the protein encoded by the open reading frame K8 of KSHV, is a member of the basic region-leucine zipper family of transcription factors. We studied the mechanisms that underlie KSHV-induced oncogenesis by investigating whether K-bZIP perturbs signaling through transforming growth factor beta (TGF-beta), which inhibits proliferation of a wide range of cell types. K-bZIP repressed TGF-beta-induced, Smad-mediated transcriptional activity and antagonized the growth-inhibitory effects of TGF-beta. Since both K-bZIP and Smad are known to interact with CREB-binding protein (CBP), the effect of CBP on inhibition of Smad-mediated transcriptional activation by K-bZIP was examined. K-bZIP mutants, which lacked the CBP-binding site, could not repress TGF-beta-induced or Smad3-mediated transcriptional activity. Overexpression of CBP restored K-bZIP-induced inhibition of Smad3-mediated transcriptional activity. Competitive interaction studies showed that K-bZIP inhibited the interaction of Smad3 with CBP. These results suggest that K-bZIP, through its binding to CBP, disrupts TGF-beta signaling by interfering with the recruitment of CBP into transcription initiation complexes on TGF-beta-responsive elements. We propose a possibility that K-bZIP may contribute to oncogenesis through its ability to promote cell survival by repressing TGF-beta signaling.
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara 903-0215, Japan.
Mariko
M
Tomita
Joonho
J
Choe
Tomoo
T
Tsukazaki
Naoki
N
Mori
D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors; D050882:CREB-Binding Protein; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein; D051901:Smad4 Protein; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism / Q000502:physiology*
D050976:Basic-Leucine Zipper Transcription Factors; D002352:Carrier Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; C118265:K8 protein, Human herpesvirus 8; D009687:Nuclear Proteins; D012097:Repressor Proteins; C497782:SMAD2 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D014764:Viral Proteins; D050882:CREB-Binding Protein; C494363:CREBBP protein, human