Gadd45β is an inducible coactivator of transcription that facilitates rapid liver growth in mice

Abstract

The growth arrest and DNA damage-inducible 45 (Gadd45) proteins act in many cellular processes. In the liver, Gadd45b (encoding Gadd45β) is the gene most strongly induced early during both compensatory regeneration and drug-induced hyperplasia. The latter response is associated with the dramatic and rapid hepatocyte growth that follows administration of the xenobiotic TCPOBOP (1,4-bis[2-(3,5)-dichoropyridyloxy] benzene), a ligand of the nuclear receptor constitutive androstane receptor (CAR). Here, we have shown that Gadd45b -/-mice have intact proliferative responses following administration of a single dose of TCPOBOP, but marked growth delays. Moreover, early transcriptional stimulation of CAR target genes was weaker in Gadd45b -/-mice than in wild-type animals, and more genes were downregulated. Gadd45β was then found to have a direct role in transcription by physically binding to CAR, and TCPOBOP treatment caused both proteins to localize to a regulatory element for the CAR target gene cytochrome P450 2b10 (Cyp2b10). Further analysis defined separate Gadd45β domains that mediated binding to CAR and transcriptional activation. Although baseline hepatic expression of Gadd45b was broadly comparable to that of other coactivators, its 140-fold stimulation by TCPO-BOP was striking and unique. The induction of Gadd45β is therefore a response that facilitates increased transcription, allowing rapid expansion of liver mass for protection against xenobiotic insults.

Overexpression of CYB5R3 and NQO1, two NAD+‐producing enzymes, mimics aspects of caloric restriction

“…Likewise, pathways populated with genes associated with cell proliferation and cell cycle were significantly downregulated in RedTg livers, a finding that was independently validated by the analysis of Gadd45b mRNA expression. Interestingly, reports have shown the existence of cross talk between the TNFα‐NFkB signaling pathway and the coactivator Gadd45β (Kodama & Negishi, 2011; Tian et al., 2011), and strong staining of GADD45β has also been detected in multiple human cancer tissues (Hoffman & Liebermann, 2013). Reciprocal regulation of the putative tumor suppressor gene Tsc22d1 , which leads to the suppression of Gadd45b and that of other cancer‐associated target genes (Iida, Anna, Gaskin, Walker & Devereux, 2007), may also account for the lower rate of tumor progression in RedTg livers.…”

Ing1 functions in DNA demethylation by directing Gadd45a to H3K4me3

“…Indeed, another determinant for DNA demethylation appears to be low-level transcription (D'Alessio et al 2007;Le May et al 2010), and in the case of rDNA promoter demethylation, this involves Gadd45a recruitment via Taf12 to RNA polymerase I (Schmitz et al 2009). Another class of Gadd45-binding cofactors that may target demethylation are nuclear hormone receptors (Ito et al 2007;Le May et al 2010;Cortellino et al 2011;Tian et al 2011;Zhang et al 2011). A further determinant may be the presence of 5mC.…”

Genome-Wide Analysis of Chromatin States Reveals Distinct Mechanisms of Sex-Dependent Gene Regulation in Male and Female Mouse Liver

“…Gene sets that respond to activators of the nuclear receptors constitutive androstane receptor (CAR) (54,55), pregnane X receptor (PXR) (54), and peroxisome proliferator-activated receptor alpha (PPAR␣) and PPAR␤/␦ (56) and to activators of AhR (57) were obtained from the indicated references. For CAR, the union of CARupregulated genes from Tojima et al (54) and Tian et al (55) was considered, with a corresponding set used for CAR downregulated genes. Genes up-or downregulated by each of the receptors were tested for enrichment for one of the six clusters (see Fig.…”