title: Reduction of transforming growth factor-beta type II receptor is caused by the enhanced ubiquitin-dependent degradation in human renal cell carcinoma.
abstract: Although dysregulation of transforming growth factor-beta (TGF-beta) signaling is implicated in renal carcinogenesis, its precise mechanism is unknown in renal cell carcinoma (RCC). In our study, we investigated Smad-mediated TGF-beta signaling pathway and its regulatory mechanisms in surgical samples from patients with RCC. We found that immunoreactivity for nuclear phosphorylated Smad2 was significantly decreased in RCC compared to normal renal tissues, thereby TGF-beta signaling was suggested to be attenuated in RCC tissues. In accordance with the result, transcriptional downregulation of Smad4 and post-transcriptional downregulation of TGF-beta type II receptor (TbetaR-II) were frequently found in RCC tissues compared to normal renal tissues. Next, to clarify the reason why the protein level of TbetaR-II was decreased in RCC, we investigated the activities of degradation and ubiquitination of TbetaR-II. We found that both proteasome-mediated degradation and ubiquitination of TbetaR-II were markedly enhanced in RCC tissues. Moreover, we found that the level of Smad-ubiquitination regulatory factor 2 (Smurf2), the E3 ligase for TbetaR-II, was increased in RCC tissues of the patients with higher clinical stages compared to the normal tissues and was inversely correlated with the level of TbetaR-II. Our results suggest that the low TbetaR-II protein level is due to augmented ubiquitin-dependent degradation via Smurf2 and might be involved in the attenuation of TGF-beta signaling pathway in RCC.
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan. hfuka@hama-med.ac.jp
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Fukasawa
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Fujigaki
authors.forename: Taro
authors.initials: T
authors.lastname: Misaki
authors.forename: Naro
authors.initials: N
authors.lastname: Ohashi
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Takayama
authors.forename: Sayuri
authors.initials: S
authors.lastname: Suzuki
authors.forename: Soichi
authors.initials: S
authors.lastname: Mugiya
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Oda
authors.forename: Chiharu
authors.initials: C
authors.lastname: Uchida
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kitagawa
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hattori
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Hayashi
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Ozono
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kitagawa
authors.forename: Akira
authors.initials: A
authors.lastname: Hishida
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D015398:Signal Transduction; D051901:Smad4 Protein / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000502:physiology; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018125:Receptors, Transforming Growth Factor beta; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II