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Transforming growth factor-? adaptor, ?2-spectrin, modulates cyclin dependent kinase 4 to reduce development of hepatocellular cancer.

ABSTRACT: Transforming growth factor beta (TGF-?) is an important regulator of cell growth, and loss of TGF-? signaling is a hallmark of carcinogenesis. The Smad3/4 adaptor protein ?2-spectrin (?2SP) is emerging as a potent regulator of tumorigenesis through its ability to modulate the tumor suppressor function of TGF-?. However, to date the role of the TGF-? 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 ?2SP, a crucial Smad3 adaptor, modulates cyclin dependent kinase 4 (CDK4), cell cycle progression, and suppression of HCC. Increased expression of ?2SP 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 ?2SP efficiently restores Rb hypophosphorylation and cell cycle arrest in G(1) . We further demonstrate that ?2SP interacts with CDK4 and Smad3 in a competitive and TGF-?-dependent manner. In addition, haploinsufficiency of cdk4 in ?2sp(+/-) mice results in a dramatic decline in HCC formation compared to that observed in ?2sp(+/-) mice.?2SP 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 ?2sp(+/-) mice as a model of preclinical efficacy in the treatment of HCC.

SUBMITTER: Baek HJ

PROVIDER: S-EPMC3162321 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Transforming growth factor-β adaptor, β2-spectrin, modulates cyclin dependent kinase 4 to reduce development of hepatocellular cancer.

Baek Hye Jung HJ Pishvaian Michael J MJ Tang Yi Y Kim Tae Hyun TH Yang Shaoxian S Zouhairi Majed El ME Mendelson Jon J Shetty Kirti K Kallakury Bhaskar B Berry Deborah L DL Shin Kyung Hwan KH Mishra Bibhuti B Reddy E Premkumar EP Kim Sang Soo SS Mishra Lopa L

Hepatology (Baltimore, Md.) 20110501 5

<h4>Unlabelled</h4>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 activa ...[more]

PMID: 21520178

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Project description:ObjectivesCyclin-dependent kinase 19 (CDK19) is a component of the mediator coactivator complex, which is required for transcriptional activation. In this study, we utilized public databases and wet-bench hepatic cell line experiments to elucidate the potential roles of CDK19 in hepatocellular cancer (HCC).Materials and methodsWe studied the relationships between CDK19 expression and several clinical features related to HCC via the Oncomine and UALCAN databases. The prognostic value of CDK19 was tested using the Kaplan-Meier Plotter database. We presented the mutations of CDK19 and addressed the relation of CDK19 expression with immune cell infiltration by means of the cBioPortal, Catalogue of Somatic Mutations in Cancer (COSMIC) and Tumor IMmune Estimation Resource (TIMER) databases. Hub genes were obtained and further analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. To test the in silico findings, we knocked down CDK19 with short hairpin RNA (shRNA) technology in two hepatic cell lines and conducted several functional characterization experiments.ResultsMarked CDK19 upregulation was found in HCC tissues versus normal liver tissues, and CDK19 mRNA expression had high diagnostic value in HCC patients. Subgroup analysis showed that CDK19 overexpression was associated with sex, tumor stage and TP53 mutation status. The prognostic value of CDK19 upregulation for overall survival (OS) was significant in patients with stage 2-3, stage 3-4, and grade 2 disease. One percent of the patients had CDK19 mutations, but no relationship between CDK19 mutation and prognosis was observed. CDK19 was positively correlated with the abundances of CD4 + T cells, macrophages and dendritic cells. We identified 10 genes correlated with CDK19, 8 of which presented excellent prognostic value in HCC. These hub genes were directly involved in cell division and regulation of the G2/M cell cycle transition. Protein-protein interaction (PPI) and pathway predictions indicated that CDK19 is highly likely to be involved in several cellular functions, such as proliferation, migration, and invasion. These functions were strongly interfered from two independent hepatic cell lines after CDK19 knockdown.ConclusionsCDK19 could be a prognostic marker in HCC, and its therapeutic potential in HCC needs further study.

Dataset Information

Transforming growth factor-? adaptor, ?2-spectrin, modulates cyclin dependent kinase 4 to reduce development of hepatocellular cancer.

Publications

Transforming growth factor-β adaptor, β2-spectrin, modulates cyclin dependent kinase 4 to reduce development of hepatocellular cancer.

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