Phosphorylation of Rat Serine 105 or Mouse Threonine 217 in C/EBPβ Is Required for Hepatocyte Proliferation Induced by TGFα

Abstract

We report that TGF alpha induces activation of the p90 ribosomal S kinase (RSK), which results in the phosphorylation of rat C/EBP beta on Ser-105 and of mouse C/EBP beta on Thr-217 and concomitantly stimulates proliferation in differentiated hepatocytes. Moreover, C/EBP beta-/- mouse hepatocytes respond to TGF alpha when wild-type C/EBP beta is reexpressed, whereas they remain refractory to the growth effect of TGF alpha when expressing phosphoacceptor mutants rat C/EBP beta Ala-105 or mouse C/EBP beta Ala-217. In contrast, C/EBP beta-/- hepatocytes expressing the phosphorylation mimic mutants, rat C/EBP beta Asp-105 or mouse C/EBP beta Glu-217, exhibited marked proliferation in the absence of TGF alpha. Thus, a site-specific phosphorylation of the transcription factor C/EBP beta is critical for hepatocyte proliferation induced by TGF alpha and other stimuli that activate RSK.

CCAAT/enhancer binding protein beta (C/EBPβ)-2 transforms normal mammary epithelial cells and induces epithelial to mesenchymal transition in culture

“…C/EBPb-null mice are completely refractory to carcinogen-induced skin tumors involving mutant Ras. Additionally, C/EBPb-null hepatocytes fail to respond to transforming growth factor alpha (TGFa), and posthepatectomy DNA synthesis is decreased to 25% of normal in C/EBPb-null mice (Buck et al, 1999). Buck et al (2001) have also shown that phosphorylation of C/EBPb on mouse/human threonine 217 or rat serine 105 by TGFa-activated ribosomal protein S-6 kinase (p90-RSK) is required for the proliferative response of primary mouse hepatocytes to TGFa.…”

Signal Transduction in the Liver: C/Ebpβ Modulates Cell Proliferation and Survival

“…1). In turn, phosphorylation of the basic domain/leucine zipper (bZip) CCAAT/enhancer binding protein (C/EBP)-␤ by RSK regulates cell proliferation and survival 9,10 (Fig. 1).…”

“…31 In addition to its role as a transactivator of many genes, [33][34][35] C/EBP␤ (originally cloned as LAP, NF-IL6, and IL-6DBP) 33,34,36 arrests the progression of the cell cycle from G1 to S-phase in hepatoma cells 37 and mediates the proliferative effects of oxidative stress and TGF-␣ in colonic cancer cells 38 and primary mouse hepatocytes. 9 Lipopolysaccharide (LPS)-stimulated factors appear to regulate the selection of AUG start sites for both activation and repression of messenger RNA (mRNA) translation from the 5 C/EBP␣ and 3 C/EBP␤ AUG codons. 39 The liver inhibitor protein (LIP), an alternative, shorter translation product initiated at the third AUG codon of the C/EBP␤ mRNA, behaves as a C/EBP␤ transcription antagonist since it shares with C/EBP␤ the DNA binding and leucine zipper domains but lacks the transactivation domain.…”

The constitutive activation of the CEF-4/9E3 chemokine gene depends on C/EBPβ in v-src transformed chicken embryo fibroblasts

“…C/ EBPb de®cient mice show defects in epithelial cell proliferation in the mammary gland and have a restricted liver regeneration capacity following partial hepatectomy (Greenbaum et al, 1998;Robinson et al, 1998;Seagroves et al, 2000). More recently, Buck and co-workers demonstrated that hepatocytes from C/ EBPb (7/7) mice do not respond to mitogenic stimulation by TGFa (Buck et al, 1999). Moreover, these authors showed that the phosphorylation and potentiation of C/EBPb transcriptional activity by pp90 RSK Oncogene Activation of CEF-4/9E3 by C/EBPb M Gagliardi et al is required for the stimulation of hepatocyte proliferation by TGFa.…”