Expression of the α7 Isoform of Hepatocyte Nuclear Factor (HNF) 4 Is Activated by HNF6/OC-2 and HNF1 and Repressed by HNF4α1 in the Liver

Briançon, Nadège; Bailly, Alain; Clotman, Frédéric; Jacquemin, Patrick; Lemaigre, Frédéric P.; Weiss, Mary C.

doi:10.1074/jbc.m405312200

Cited by 67 publications

(70 citation statements)

References 83 publications

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“…3F). In contrast, there was a marked decrease in P2-HNF4α protein upon PP2 treatment, which could be due to the fact that P1-HNF4α is known to decrease transcription of the P2 promoter (21). All told, selective phosphorylation of endogenous P1-HNF4α in a colon cancer cell line correlates with decreased protein stability and is consistent with the experiments using ectopic expression and phosphomimetic mutants.…”

Section: Phosphomimetic Mutants Of P1-hnf4α Negatively Affect Proteinsupporting

confidence: 83%

“…S1). While only P1-driven HNF4α (P1-HNF4α) is expressed in the adult liver, both P1-and P2-driven HNF4α (P2-HNF4α) are expressed in the adult intestine and colon (21,22). Expression of P1-HNF4α is decreased in several human cancers including hepatocellular, gastric, renal, and colorectal carcinomas, while the expression of P2-HNF4α is either unchanged or upregulated (22,23).…”

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confidence: 99%

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Src tyrosine kinase phosphorylation of nuclear receptor HNF4α correlates with isoform-specific loss of HNF4α in human colon cancer

Chellappa

Jankova²,

Schnabl³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

109

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Src tyrosine kinase has long been implicated in colon cancer but much remains to be learned about its substrates. The nuclear receptor hepatocyte nuclear factor 4α (HNF4α) has just recently been implicated in colon cancer but its role is poorly defined. Here we show that c-Src phosphorylates human HNF4α on three tyrosines in an interdependent and isoform-specific fashion. The initial phosphorylation site is a Tyr residue (Y14) present in the N-terminal A/B domain of P1-but not P2-driven HNF4α. Phospho-Y14 interacts with the Src SH2 domain, leading to the phosphorylation of two additional tyrosines in the ligand binding domain (LBD) in P1-HNF4α. Phosphomimetic mutants in the LBD decrease P1-HNF4α protein stability, nuclear localization and transactivation function. Immunohistochemical analysis of approximately 450 human colon cancer specimens (Stage III) reveals that P1-HNF4α is either lost or localized in the cytoplasm in approximately 80% of tumors, and that staining for active Src correlates with those events in a subset of samples. Finally, three SNPs in the human HNF4α protein, two of which are in the HNF4α F domain that interacts with the Src SH3 domain, increase phosphorylation by Src and decrease HNF4α protein stability and function, suggesting that individuals with those variants may be more susceptible to Src-mediated effects. This newly identified interaction between Src kinase and HNF4α has important implications for colon and other cancers.HNF4 isoforms | SH2 SH3 domain | SNP | Src kinase | tyrosine phosphorylation C olon cancer, the third most common malignancy in the United States, is a multifactorial disease that is influenced by both genetics and the environment (1, 2). c-Src is a nonreceptor tyrosine kinase that is strongly implicated in the development, growth, progression, and metastasis of several human cancers (3). In colon cancer, Src activation is associated with the early stages (4, 5) as well as progression and metastasis (6-8). Despite this long association with colon cancer, much remains to be learned about Src substrates (9).Hepatocyte nuclear factor 4alpha (HNF4α) (NR2A1) is a highly conserved member of the nuclear receptor superfamily with a recently identified endogenous ligand (linoleic acid) that binds in a reversible fashion (10, 11). HNF4α is best known for its role as a master regulator of liver-specific gene expression and as a key player in beta cells of the pancreas where it is mutated in an inherited form of type 2 diabetes (12)(13)(14). HNF4α is also expressed in kidney, stomach, and intestine; several recent papers also show an important role for HNF4α in the colon (15-20). There are two different promoters (P1 and P2) of HNF4A that are utilized in a temporal and tissue-specific fashion (11) (Fig. S1). While only P1-driven HNF4α (P1-HNF4α) is expressed in the adult liver, both P1-and P2-driven HNF4α (P2-HNF4α) are expressed in the adult intestine and colon (21, 22). Expression of P1-HNF4α is decreased in several human cancers including hepatocellular, gastric, renal, and...

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Section: Phosphomimetic Mutants Of P1-hnf4α Negatively Affect Proteinsupporting

confidence: 83%

mentioning

confidence: 99%

Src tyrosine kinase phosphorylation of nuclear receptor HNF4α correlates with isoform-specific loss of HNF4α in human colon cancer

Chellappa

Jankova²,

Schnabl³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

109

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“…The proximal P1 promoter drives the expression of the major isoforms in the adult hepatocyte, intestine and kidney (primarily HNF4α1 and HNF4α2); HNF4α2 differs from HNF4α1 by a 10 amino acid insertion in the C-terminal region (see Figure 1C). The distal P2 promoter drives the expression of isoforms present primarily in the embryonic liver and adult stomach and pancreas (primarily HNF4α7/8); HNF4α7/8 are 13 amino acids shorter than HNF4α1/2 due to a different N-terminus [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Tumour suppressor p53 down-regulates the expression of the human hepatocyte nuclear factor 4α (HNF4α) gene

Maeda

Hwang‐Verslues

Wei

et al. 2006

Biochemical Journal

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The liver is exposed to a wide variety of toxic agents, many of which damage DNA and result in increased levels of the tumour suppressor protein p53. We have previously shown that p53 inhibits the transactivation function of HNF (hepatocyte nuclear factor) 4α1, a nuclear receptor known to be critical for early development and liver differentiation. In the present study we demonstrate that p53 also down-regulates expression of the human HNF4α gene via the proximal P1 promoter. Overexpression of wild-type p53 down-regulated endogenous levels of both HNF4α protein and mRNA in Hep3B cells. This decrease was also observed when HepG2 cells were exposed to UV irradiation or doxorubicin, both of which increased endogenous p53 protein levels. Ectopically expressed p53, but not a mutant p53 defective in DNA binding (R249S), down-regulated HNF4α P1 promoter activity. Chromatin immunoprecipitation also showed that endogenous p53 bound the HNF4α P1 promoter in vivo after doxorubicin treatment. The mechanism by which p53 down-regulates the P1 promoter appears to be multifaceted. The down-regulation was partially recovered by inhibition of HDAC activity and appears to involve the positive regulator HNF6α. p53 bound HNF6α in vivo and in vitro and prevented HNF6α from binding DNA in vitro. p53 also repressed stimulation of the P1 promoter by HNF6α in vivo. However, since the R249S p53 mutant also bound HNF6α, binding HNF6α is apparently not sufficient for the repression. Implications of the p53-mediated repression of HNF4α expression in response to cellular stress are discussed.

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“…Hepatocyte nuclear factor 6 (HNF-6, also called Onecut-1), a member of the Onecut family of transcriptional activators, belongs to the LETF network (4,22,27,33). It is expressed in the hepatic epithelial cells, i.e., in the hepatoblasts and then in the cholangiocytes and hepatocytes, where it persists in adults.…”

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confidence: 99%

Threshold Levels of Hepatocyte Nuclear Factor 6 (HNF-6) Acting in Synergy with HNF-4 and PGC-1α Are Required for Time-Specific Gene Expression during Liver Development

Beaudry

Pierreux

Hayhurst

et al. 2006

Molecular and Cellular Biology

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During liver development, hepatocytes undergo a maturation process that leads to the fully differentiated state. This relies at least in part on the coordinated action of liver-enriched transcription factors (LETFs), but little is known about the dynamics of this coordination. In this context we investigate here the role of the LETF hepatocyte nuclear factor 6 (HNF-6; also called Onecut-1) during hepatocyte differentiation. We show that HNF-6 knockout mouse fetuses have delayed expression of glucose-6-phosphatase (g6pc), which catalyzes the final step of gluconeogenesis and is a late marker of hepatocyte maturation. Using a combination of in vivo and in vitro gain-and loss-of-function approaches, we demonstrate that HNF-6 stimulates endogenous g6pc gene expression directly via a synergistic and interdependent action with HNF-4 and that it involves coordinate recruitment of the coactivator PGC-1␣. The expression of HNF-6, HNF-4, and PGC-1␣ rises steadily during liver development and precedes that of g6pc. We provide evidence that threshold levels of HNF-6 are required to allow synergism between HNF-6, HNF-4, and PGC-1␣ to induce time-specific expression of g6pc. Our observations on the regulation of g6pc by HNF-6 provide a model whereby synergism, interdependency, and threshold concentrations of LETFs and coactivators determine time-specific expression of genes during liver development.

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Expression of the α7 Isoform of Hepatocyte Nuclear Factor (HNF) 4 Is Activated by HNF6/OC-2 and HNF1 and Repressed by HNF4α1 in the Liver

Cited by 67 publications

References 83 publications

Src tyrosine kinase phosphorylation of nuclear receptor HNF4α correlates with isoform-specific loss of HNF4α in human colon cancer

Src tyrosine kinase phosphorylation of nuclear receptor HNF4α correlates with isoform-specific loss of HNF4α in human colon cancer

Tumour suppressor p53 down-regulates the expression of the human hepatocyte nuclear factor 4α (HNF4α) gene

Threshold Levels of Hepatocyte Nuclear Factor 6 (HNF-6) Acting in Synergy with HNF-4 and PGC-1α Are Required for Time-Specific Gene Expression during Liver Development

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