Cell cycle deregulation by the HBx protein of hepatitis B virus

Autores/as

  • Vijay Kumar International Centre for Genetic Engineering and Biotechnology

Resumen


Cell cycle control by oncogenic viruses usually involves disruption of the normal restraints on cellular proliferation via abnormal proteolytic degradation and malignant transformation of cells. The cell cycle regulatory molecules viz. cyclins, cyclin-dependent kinases (cdks) and inhibitors of cdks as well as the transcriptional targets of signaling pathways induce cells to move through the cell cycle checkpoints. These check points are often found deregulated in tumor cells and in the cells afflicted with DNA tumor viruses predisposing them towards transformation. The X protein or HBx of hepatitis B virus is a promiscuous transactivator that has been implicated in the development of hepatocellular carcinoma in humans. However, the exact role of HBx in establishing a permissive environment for hepatocarcinogenesis is not fully understood. HBx activates the Ras-Raf-MAP kinase signaling cascade, through which it activates transcription factors AP-1 and NFkappa B, and stimulates cell DNA synthesis. HBx shows a profound effect on cell cycle progression even in the absence of serum. It can override the replicative senescence of cells in G0 phase by binding to p55sen. It stimulates the G0 cells to transit through G1 phase by activating Src kinases and the cyclin A-cyclin-dependent kinase 2 complexes, that in turn induces the cyclin A promoter. There is an early and sustained level of cyclin-cdk2 complex in the presence of HBx during the cell cycle which is coupled with an increased protein kinase activity of cdk2 suggesting an early appearance of S phase. The interaction between cyclin-cdk2 complex and HBx occurs through its carboxyterminal region (amino acids 85-119) and requires a constitutive Src kinase activity. The increased cdk2 activity is associated with stabilization of cyclin E as well as proteasomal degradation of cdk inhibitor p27Kip1. Notably, the HBx mutant that fails to interact with cyclin-cdk2 complex, also fails to destabilize p27Kip1 or deregulate cell cycle. Thus, HBx appears to override normal cell cycle restraints by directly interacting with the key cell cycle regulators and modu lating their activities. These data suggest a molecular mechanism by which HBx likely contributes to viral carcinogenesis. Driving the HBV-infected cells to grow continuously may be essential for active viral replication that could facilitate the full manifestation of the oncogenic potential of HBx.

 

BIBLIOGRAFÍA

1. Benn J, Schneider RJ. (1995) Hepatitis B virus HBx protein deregulates cell cycle checkpoint controls. Proc Natl Acad Sci USA 92, 11215-11219.

2. Bouchard M, Giannakopoulos S, Wang EH, Tanese N, Schneider RJ (2001) Hepatitis B virus HBx protein activation of cyclin A-cyclin-dependent kinase 2 complexes and G1 transit via a Src kinase pathway. J Virol 75, 4247-4257.

3. Lee S, Tarn C, Wang WH, Chen S, Hullinger RL, Andrisani OM (2002) Hepatitis B virus X protein differentially regulates cell cycle progression in X-transforming versus nontransforming hepatocyte (AML12) cell lines. J Biol Chem 277, 8730-8740.

4. Mukherji A, Janbandhu VC, Kumar V. (2007) HBx-dependent cell cycle deregulation involves interaction with cyclin E/A-cdk2 complex and destabilization of p27Kip1. Biochem J 401, 247-256.

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Biografía del autor/a

Vijay Kumar, International Centre for Genetic Engineering and Biotechnology

Scientist, Virology Group, International Centre for Genetic Engineering and Biotechnology, INDIA.

Publicado

2007-02-08

Cómo citar

1.
Kumar V. Cell cycle deregulation by the HBx protein of hepatitis B virus. Iatreia [Internet]. 8 de febrero de 2007 [citado 2 de julio de 2022];20(2-S):S-29. Disponible en: https://revistas.udea.edu.co/index.php/iatreia/article/view/4362

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