| First Author | Dahan J | Year | 2013 |
| Journal | Mol Cell Biol | Volume | 33 |
| Issue | 16 | Pages | 3299-308 |
| PubMed ID | 23775124 | Mgi Jnum | J:204718 |
| Mgi Id | MGI:5538468 | Doi | 10.1128/MCB.00105-13 |
| Citation | Dahan J, et al. (2013) LIM-only protein FHL2 activates NF-kappaB signaling in the control of liver regeneration and hepatocarcinogenesis. Mol Cell Biol 33(16):3299-308 |
| abstractText | Four-and-a-half LIM-only protein 2 (FHL2) is an important mediator in many signaling pathways. In this study, we analyzed the functions of FHL2 in nuclear factor kappaB (NF-kappaB) signaling in the liver. We show that FHL2 enhanced tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) activity in transcriptional activation of NF-kappaB targets by stabilizing the protein. TRAF6 is a binding partner of FHL2 and an important component of the Toll-like receptor-NF-kappaB pathway. Knockdown of FHL2 in 293-hTLR4/MD2-CD14 cells impaired lipopolysaccharide (LPS)-induced NF-kappaB activity, which regulates expression of inflammatory cytokines. Indeed, FHL2(-/-) macrophages showed significantly reduced production of TNF and interleukin 6 (IL-6) following LPS stimulation. TNF and IL-6 are the key cytokines that prime liver regeneration after hepatic injury. Following partial hepatectomy, FHL2(-/-) mice exhibited diminished induction of TNF and IL-6 and delayed hepatocyte regeneration. In the liver, NF-kappaB signaling orchestrates inflammatory cross talk between hepatocytes and hepatic immune cells that promote chemical hepatocarcinogenesis. We found that deficiency of FHL2 reduced susceptibility to diethylnitrosamine-induced hepatocarcinogenesis, correlating with the activator function of FHL2 in NF-kappaB signaling. Our findings demonstrate FHL2 as a positive regulator of NF-kappaB activity in liver regeneration and carcinogenesis and highlight the importance of FHL2 in both hepatocytes and hepatic immune cells. |
