scholarly journals Repression of Hepatocyte Nuclear Factor 4α by Tumor Suppressor p53: Involvement of the Ligand-Binding Domain and Histone Deacetylase Activity

2002 ◽  
Vol 16 (2) ◽  
pp. 402-410 ◽  
Author(s):  
Yutaka Maeda ◽  
Shawn D. Seidel ◽  
Gang Wei ◽  
Xuan Liu ◽  
Frances M. Sladek
Keyword(s):  
Tumor Suppressor ◽  
Ligand Binding ◽  
Histone Deacetylase ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Tumor Suppressor P53 ◽  
Hepatocyte Nuclear Factor 4Α

scholarly journals The G115S mutation associated with maturity-onset diabetes of the young impairs hepatocyte nuclear factor 4α activities and introduces a PKA phosphorylation site in its DNA-binding domain

2004 ◽  
Vol 383 (3) ◽  
pp. 573-580 ◽  
Author(s):  
Bénédicte OXOMBRE ◽  
Mostafa KOUACH ◽  
Ericka MOERMAN ◽  
Pierre FORMSTECHER ◽  
Bernard LAINE
Keyword(s):  
Transcription Factor ◽  
Dna Binding ◽  
Transcriptional Activity ◽  
Phosphorylation Site ◽  
Binding Domain ◽  
Nuclear Factor ◽  
Dna Binding Domain ◽  
Maturity Onset Diabetes ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 4Α

HNF4α (hepatocyte nuclear factor 4α) belongs to a complex transcription factor network that is crucial for the function of hepatocytes and pancreatic β-cells. In these cells, it activates the expression of a very large number of genes, including genes involved in the transport and metabolism of glucose and lipids. Mutations in the HNF4α gene correlate with MODY1 (maturity-onset diabetes of the young 1), a form of type II diabetes characterized by an impaired glucose-induced insulin secretion. The MODY1 G115S (Gly115→Ser) HNF4α mutation is located in the DNA-binding domain of this nuclear receptor. We show here that the G115S mutation failed to affect HNF4α-mediated transcription on apolipoprotein promoters in HepG2 cells. Conversely, in pancreatic β-cell lines, this mutation resulted in strong impairments of HNF4α transcriptional activity on the promoters of LPK (liver pyruvate kinase) and HNF1α, with this transcription factor playing a key role in endocrine pancreas. We show as well that the G115S mutation creates a PKA (protein kinase A) phosphorylation site, and that PKA-mediated phosphorylation results in a decreased transcriptional activity of the mutant. Moreover, the G115E (Gly115→Glu) mutation mimicking phosphorylation reduced HNF4α DNA-binding and transcriptional activities. Our results may account for the 100% penetrance of diabetes in human carriers of this mutation. In addition, they suggest that introduction of a phosphorylation site in the DNA-binding domain may represent a new mechanism by which a MODY1 mutation leads to loss of HNF4α function.

scholarly journals Critical Role of Residues Defining the Ligand Binding Pocket in Hepatocyte Nuclear Factor-4α

2004 ◽  
Vol 279 (29) ◽  
pp. 30680-30688 ◽  
Author(s):  
Eleni Aggelidou ◽  
Panagiota Iordanidou ◽  
Panayota Tsantili ◽  
Georgios Papadopoulos ◽  
Margarita Hadzopoulou-Cladaras
Keyword(s):  
Ligand Binding ◽  
Critical Role ◽  
Binding Pocket ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Ligand Binding Pocket ◽  
Hepatocyte Nuclear Factor 4Α

Frequent mutations in the ligand-binding domain of PML-RARα after multiple relapses of acute promyelocytic leukemia: analysis for functional relationship to response to all-transretinoic acid and histone deacetylase inhibitors in vitro and in vivo

Blood ◽  
2002 ◽  
Vol 99 (4) ◽  
pp. 1356-1363 ◽  
Author(s):  
Da-Cheng Zhou ◽  
Soon H. Kim ◽  
Wei Ding ◽  
Cynthia Schultz ◽  
Raymond P. Warrell ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Histone Deacetylase ◽  
Acute Promyelocytic Leukemia ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Promyelocytic Leukemia ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Missense Mutations

This study identified missense mutations in the ligand binding domain of the oncoprotein PML-RARα in 5 of 8 patients with acute promyelocytic leukemia (APL) with 2 or more relapses and 2 or more previous courses of all-trans retinoic acid (RA)–containing therapy. Four mutations were novel (Lys207Asn, Gly289Arg, Arg294Trp, and Pro407Ser), whereas one had been previously identified (Arg272Gln; normal RARα1 codon assignment). Five patients were treated with repeat RA plus phenylbutyrate (PB), a histone deacetylase inhibitor, and one patient experienced a prolonged clinical remission. Of the 5 RA + PB-treated patients, 4 had PML-RARα mutations. The Gly289Arg mutation in the clinical responder produced the most defective PML-RARα function in the presence of RA with or without sodium butyrate (NaB) or trichostatin A. Relapse APL cells from this patient failed to differentiate in response to RA but partially differentiated in response to NaB alone, which was augmented by RA. In contrast, NaB alone had no differentiation effect on APL cells from another mutant case (Pro407Ser) but enhanced differentiation induced by RA. These results indicate that PML-RARα mutations occurred with high frequency after multiple RA treatment relapses, indicate that the functional potential of PML-RARα was not correlated with clinical response to RA + PB treatment, and suggest that the response to RA + PB therapy in one patient was related to the ability of PB to circumvent the blocked RA-regulated gene response pathway.

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