Article thumbnail

Calmodulin Controls Liver Proliferation via Interactions with C/EBPβ-LAP and C/EBPβ-LIP*

By Daniel Orellana, Xiaoying Liu, Gou-Li Wang, Jingling Jin, Polina Iakova and Nikolai A. Timchenko

Abstract

A truncated isoform of C/EBPβ, C/EBPβ-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/EBPβ-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/EBPβ-LIP. We found that calmodulin (CaM) inhibits the ability of C/EBPβ-LIP to promote liver proliferation during APR through direct interactions. This activity of CaM is under negative control of Ca2+, 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/EBPβ-LIP, also fails to inhibit the growth promotion activity of C/EBPβ-LIP. Down-regulation of CaM in livers of LPS-treated mice causes liver proliferation via activation of C/EBPβ-LIP. Overexpression of C/EBPβ-LIP above levels of CaM also initiates liver proliferation in LPS-treated mice. In addition, CaM regulates transcriptional activity of another isoform of C/EBPβ, C/EBPβ-LAP, and might control liver biology through the regulation of both isoforms of C/EBPβ. In searching for molecular mechanisms by which C/EBPβ-LIP promotes cell proliferation, we found that C/EBPβ-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/EBPβ-LIP and, therefore, supports liver quiescence. Thus, our findings discover a new pathway of the regulation of liver proliferation that involves calcium-CaM signaling

Topics: Cell Biology
Publisher: American Society for Biochemistry and Molecular Biology
OAI identifier: oai:pubmedcentral.nih.gov:2906335
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)

  • To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

    Suggested articles