HBx-dependent cell cycle deregulation involves interaction with cyclin E/A–cdk2 complex and destabilization of p27Kip1
- 11 December 2006
- journal article
- research article
- Published by Portland Press Ltd. in Biochemical Journal
- Vol. 401 (1), 247-256
- https://doi.org/10.1042/bj20061091
Abstract
The HBx (X protein of hepatitis B virus) is a promiscuous transactivator implicated to play a key role in hepatocellular carcinoma. However, HBx-regulated molecular events leading to deregulation of cell cycle or establishment of a permissive environment for hepatocarcinogenesis are not fully understood. Our cell culture-based studies suggested that HBx had a profound effect on cell cycle progression even in the absence of serum. HBx presence led to an early and sustained level of cyclin–cdk2 complex during the cell cycle combined with increased protein kinase activity of cdk2 heralding an early proliferative signal. The increased cdk2 activity also led to an early proteasomal degradation of p27Kip1 that could be reversed by HBx-specific RNA interference and blocked by a chemical inhibitor of cdk2 or the T187A mutant of p27. Further, our co-immunoprecipitation and in vitro binding studies with recombinant proteins suggested a direct interaction between HBx and the cyclin E/A–cdk2 complex. Interference with different signalling cascades known to be activated by HBx suggested a constitutive requirement of Src kinases for the association of HBx with these complexes. Notably, the HBx mutant that did not interact with cyclin E/A failed to destabilize p27Kip1 or deregulate the cell cycle. Thus HBx appears to deregulate the cell cycle by interacting with the key cell cycle regulators independent of its well-established role in transactivation.Keywords
This publication has 53 references indexed in Scilit:
- Control of the SCFSkp2–Cks1 ubiquitin ligase by the APC/CCdh1 ubiquitin ligaseNature, 2004
- Specific inhibition of gene expression and transactivation functions of hepatitis B virus X protein and c‐myc by small interfering RNAsFEBS Letters, 2004
- Recycling the Cell CycleCell, 2004
- Hepatitis B Virus X Protein Differentially Regulates Cell Cycle Progression in X-transforming Versus Nontransforming Hepatocyte (AML12) Cell LinesPublished by Elsevier BV ,2002
- Accumulation of Cyclin E Is Not a Prerequisite for Passage through the Restriction PointMolecular and Cellular Biology, 2001
- The Hepatitis B Virus-X Protein Activates a Phosphatidylinositol 3-Kinase-dependent Survival Signaling CascadeJournal of Biological Chemistry, 2001
- Molecular mechanism of cell cycle progression induced by the oncogene product Tax of human T-cell leukemia virus type IOncogene, 2001
- The Hallmarks of CancerCell, 2000
- p27Kip1 ubiquitination and degradation is regulated by the SCFSkp2 complex through phosphorylated Thr187 in p27Current Biology, 1999
- JAK2 Is Essential for Activation of c-fos and c-myc Promoters and Cell Proliferation through the Human Granulocyte-Macrophage Colony-stimulating Factor Receptor in BA/F3 CellsPublished by Elsevier BV ,1996