Calmodulin controls liver proliferation via interactions with C/EBPbeta-LAP and C/EBPbeta-LIP.
A truncated isoform of C/EBPbeta, C/EBPbeta-LIP, is required for liver proliferation. This isoform is expressed at high levels in proliferating liver and in liver tumors. However, high levels of C/EBPbeta-LIP are also observed in non-proliferating livers during acute phase response (APR). In this paper we present mechanisms by which liver regulates activities of C/EBPbeta-LIP. We found that calmodulin (CaM) inhibits the ability of C/EBPbeta-LIP to promote liver proliferation during APR through direct interactions. This activity of CaM is under negative control of Ca(2+), which is reduced in nuclei of livers with APR, whereas it is increased in nuclei of proliferating livers. A mutant CaM, which does not interact with C/EBPbeta-LIP, also fails to inhibit the growth promotion activity of C/EBPbeta-LIP. Down-regulation of CaM in livers of LPS-treated mice causes liver proliferation via activation of C/EBPbeta-LIP. Overexpression of C/EBPbeta-LIP above levels of CaM also initiates liver proliferation in LPS-treated mice. In addition, CaM regulates transcriptional activity of another isoform of C/EBPbeta, C/EBPbeta-LAP, and might control liver biology through the regulation of both isoforms of C/EBPbeta. In searching for molecular mechanisms by which C/EBPbeta-LIP promotes cell proliferation, we found that C/EBPbeta-LIP releases E2F.Rb-dependent repression of cell cycle genes by a disruption of E2F1.Rb complexes and by a direct interaction with E2F-dependent promoters. CaM inhibits these growth promotion activities of C/EBPbeta-LIP and, therefore, supports liver quiescence. Thus, our findings discover a new pathway of the regulation of liver proliferation that involves calcium-CaM signaling.
Orellana
Daniel
D
Huffington Center on Aging and Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
Liu
Xiaoying
X
Wang
Gou-Li
GL
Jin
Jingling
J
Iakova
Polina
P
Timchenko
Nikolai A
NA
D000210:Acute-Phase Reaction / Q000378:metabolism / Q000473:pathology; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D050684:E2F Transcription Factors / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D016160:Retinoblastoma Protein / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics
D022782:CCAAT-Enhancer-Binding Protein-beta; D002147:Calmodulin; D018797:Cell Cycle Proteins; D050684:E2F Transcription Factors; D008070:Lipopolysaccharides; C499306:Mybl2 protein, mouse; D016160:Retinoblastoma Protein; D015534:Trans-Activators; D002118:Calcium