title: Transforming growth factor-β adaptor, β2-spectrin, modulates cyclin dependent kinase 4 to reduce development of hepatocellular cancer.
abstract: Transforming growth factor beta (TGF-β) is an important regulator of cell growth, and loss of TGF-β signaling is a hallmark of carcinogenesis. The Smad3/4 adaptor protein β2-spectrin (β2SP) is emerging as a potent regulator of tumorigenesis through its ability to modulate the tumor suppressor function of TGF-β. However, to date the role of the TGF-β signaling pathway at specific stages of the development of hepatocellular carcinoma (HCC), particularly in relation to the activation of other oncogenic pathways, remains poorly delineated. Here we identify a mechanism by which β2SP, a crucial Smad3 adaptor, modulates cyclin dependent kinase 4 (CDK4), cell cycle progression, and suppression of HCC. Increased expression of β2SP inhibits phosphorylation of the retinoblastoma gene product (Rb) and markedly reduces CDK4 expression to a far greater extent than other CDKs and cyclins. Furthermore, suppression of CDK4 by β2SP efficiently restores Rb hypophosphorylation and cell cycle arrest in G(1) . We further demonstrate that β2SP interacts with CDK4 and Smad3 in a competitive and TGF-β-dependent manner. In addition, haploinsufficiency of cdk4 in β2sp(+/-) mice results in a dramatic decline in HCC formation compared to that observed in β2sp(+/-) mice.
  
  
  CONCLUSIONS
  β2SP deficiency leads to CDK4 activation and contributes to dysregulation of the cell cycle, cellular proliferation, oncogene overexpression, and the formation of HCCs. Our data highlight CDK4 as an attractive target for the pharmacologic inhibition of HCC and demonstrate the importance of β2sp(+/-) mice as a model of preclinical efficacy in the treatment of HCC.
authors.affiliation: Radiation Medicine Branch, National Cancer Center, Goyang, Korea.
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Baek
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pishvaian
authors.forename: Yi
authors.initials: Y
authors.lastname: Tang
authors.forename: Tae Hyun
authors.initials: TH
authors.lastname: Kim
authors.forename: Shaoxian
authors.initials: S
authors.lastname: Yang
authors.forename: Majed El
authors.initials: ME
authors.lastname: Zouhairi
authors.forename: Jon
authors.initials: J
authors.lastname: Mendelson
authors.forename: Kirti
authors.initials: K
authors.lastname: Shetty
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Kallakury
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Berry
authors.forename: Kyung Hwan
authors.initials: KH
authors.lastname: Shin
authors.forename: Bibhuti
authors.initials: B
authors.lastname: Mishra
authors.forename: E Premkumar
authors.initials: EP
authors.lastname: Reddy
authors.forename: Sang Soo
authors.initials: SS
authors.lastname: Kim
authors.forename: Lopa
authors.initials: L
authors.lastname: Mishra
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D049109:Cell Proliferation; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000502:physiology*; D057895:Haploinsufficiency; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D051900:Smad3 Protein / Q000502:physiology; D013049:Spectrin / Q000502:physiology*; D016212:Transforming Growth Factor beta
chemical_list: D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D013049:Spectrin; D051358:Cyclin-Dependent Kinase 4