HBx function as signaling molecule
HBx has been described as modulating many signaling pathways. It is unlikely that the 154aa protein is able to bind specific partners and play a role directly in all these pathways. Presumably it acts on few key modulators of these pathways.
A) Cytoplasmic signaling pathways:
HBx has the capacity to modulate many cytoplasmic signaling pathways since it has been shown to up-regulate Src/Ras, SAPK/JNK, AKT/PKB, NF-kB, Janus kinase/STAT, PKC, PI3-K, FAK, PyK-2, p53 signaling transduction pathways (Wei et al. 2010) Rating=Review.
NF-kB-linked signaling pathways:
- HBx activates the Src-Ras-Raf-MEK-ERK pathway (Klein et al. 1999) Rating=2. Activation of Src signaling pathway enhances androgen receptor (AR)-mediated activity in the host, which might be the explanation for male predominance of HCC (male to female ratio about 6:1) (Chiu et al. 2007) Rating=1.
- Src pathway could be turned on by the focal adhesion kinase (FAK) or proline-rich kinase 2 ((Pyk)2) following HBx-induced release of calcium into the cytoplasm from intracellular calcium stores. FAK would then activate Src kinases and downstream signal transduction (NF-kB, AP-1-dependent transcription) and HBV DNA replication (Bouchard et al. 2006) Rating=1, (Bouchard et al. 2001) Rating=1.
- HBx activates a PI3-K dependent signaling pathway (Lee et al. 2001) Rating=1.
- HBx has been shown to induce activation of IkB kinase (IKK)/NF-kB signaling pathway. Increased levels of NF-kB have been related to HBx-mediated ubiquitination and nuclear translocation of IKK-alpha via AKT-dependent phosphorylation (Huang et al. 2011) Rating=2 and to HBx-induced up-regulation of TBK1 (Kim et al. 2010) Rating=1.
- There is a positive feedback loop between TNF-alpha/NF-kB and HBx (Shukla et al. 2011) Rating=1.
HBV seems to trigger inter-related pathways. Possible aims could be to promote cell survival and/or optimal viral DNA replication. According to all concerned up-regulated proteins, FAK family kinases, including FAK and (Pyk)2, could be one of the target of HBx since they could on one hand activate PI3-K via Src kinases, leading to activation of AKT and subsequently of IKKb and NF-kB.
Antiapoptotic signaling pathways:
- HBx prevents apoptosis in normal cells through inhibition of pro-apoptotic p53 protein via direct interaction in the cytoplasm, sequestering and preventing p53 entry into the nucleus (Shukla et al. 2011) Rating=2. In addition, co-action with anti-apoptotic delta-TAp73 favors cell survival (PubMed 22030623) Rating=2.
- MEKK1, SEK1, SAPK, 14-3-3 protein, and HBx have been shown to form a complex in the cytoplasm thereby activating SAPK/JNK activity and suppression of Fas-mediated apoptosis (Diao et al. 2001) Rating=2.
HBx has been reported to modulate apoptosis. Pro- or anti-apoptotic effects are probably cell context dependent, with HBx inducting apoptosis in transformed cells and inhibiting it in normal hepatocytes.
Might also achieves protection against apoptotic death through an HBx-P3K-AKT-Bad pathway and by inactivating caspase 3 activity, or in association with H-ras oncogene through activation of the phosphatidyl inositol-3 kinase and AKT pathway.
Cell cycle deregulation
- HBx activates the Wnt/beta-catenin signaling pathway by competitively binding APC to displace beta-catenin from its degradation complex. This leads to beta-catenin upregulation in the nucleus (Hsieh et al. 2011) Rating=1. Elevated beta-catenin level results in hyperactivated transcription of cyclin D, VEGF, and c-MYC, which could promote malignancy. Increased expression of beta-catenin in the cytoplasm or nucleus occurs in 50-70% of HCC patients, and its elevated level might thus play a role in HCC development (Suzuki et al. 2002) Rating=1.
- HBx, through its interaction with HBXIP, could deregulate centrosome duplication (Garcia-Saez et al. 2011, Wen et al. 2008) Rating=1.
- HBx might induce quiescent hepatocytes to enter the G1 phase of the cell cycle (Gearhart et al. 2010) Rating=1. This might be linked to HBx elevation of cytosolic calcium via release of calcium from intracellular calcium stores (Yang et al. 2011) Rating=1
- HBx might also be involved in deregulating the mitotic checkpoint and thus induce aberrant chromosomal segregation (Kim et al. 2008) Rating=1
B) Nuclear genes transactivation:
HBx performs transactivation by up-regulating the activity of a number of transcription factors such as nuclear factor kappa B (NF-kB), AP-1, AP-2, c-EBP, CREB/ ATF, SP1, HIF-a, E2F, NF-AT , (Diao et al. 2001). Interaction of HBx with the acetyltransferases CBP/p300 plays a central role in the activation of CREB-dependent transcription. Upregulating the activity of AP-1 might explain how HBx activates the transcription of DNMT1 (cf. HBx-induced DNA methylation).