Hepatocyte nuclear factor 4 alpha

Hepatocyte nuclear factor 4, alpha

PDB rendering based on 1m7w.

Available structures
PDB	1PZL, 3CBB, 3FS1

Identifiers

Symbols

HNF4A; FLJ39654; HNF4; HNF4a7; HNF4a8; HNF4a9; HNF4alpha; MODY; MODY1; NR2A1; NR2A21; TCF; TCF14

External IDs

OMIM: 600281 MGI: 109128 HomoloGene: 395 IUPHAR: NR2A1 GeneCards: HNF4A Gene

Gene Ontology
Molecular function	• fatty-acyl-CoA binding • RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription • DNA binding • sequence-specific DNA binding transcription factor activity • sequence-specific enhancer binding RNA polymerase II transcription factor activity • steroid hormone receptor activity • receptor binding • fatty acid binding • protein binding • zinc ion binding • palmitoyl-CoA hydrolase activity • activating transcription factor binding • protein homodimerization activity • sequence-specific DNA binding • transcription regulatory region DNA binding • metal ion binding • repressing transcription factor binding
Cellular component	• nucleus • nucleoplasm • transcription factor complex • cytoplasm
Biological process	• transcription, DNA-dependent • regulation of transcription from RNA polymerase II promoter • regulation of transcription from RNA polymerase II promoter • ornithine metabolic process • acyl-CoA metabolic process • xenobiotic metabolic process • establishment of tissue polarity • sex differentiation • blood coagulation • negative regulation of cell proliferation • response to glucose stimulus • gene expression • regulation of gastrulation • regulation of lipid metabolic process • cell differentiation • negative regulation of cell growth • endocrine pancreas development • regulation of microvillus assembly • negative regulation of protein import into nucleus, translocation • regulation of transcription from RNA polymerase II promoter by nuclear hormone receptor • response to drug • negative regulation of tyrosine phosphorylation of Stat5 protein • glucose homeostasis • negative regulation of sequence-specific DNA binding transcription factor activity • cell-cell junction organization • positive regulation of gluconeogenesis • positive regulation of fatty acid biosynthetic process • positive regulation of transcription, DNA-dependent • negative regulation of mitotic cell cycle • positive regulation of transcription from RNA polymerase II promoter • positive regulation of transcription from RNA polymerase II promoter • positive regulation of transcription from RNA polymerase II promoter • negative regulation of peptidyl-tyrosine phosphorylation • regulation of insulin secretion • response to cAMP • lipid homeostasis • phospholipid homeostasis • SMAD protein signal transduction • regulation of growth hormone receptor signaling pathway • triglyceride homeostasis • positive regulation of cholesterol homeostasis
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 20:
42.98 – 43.06 Mb

Chr 2:
163.33 – 163.4 Mb

PubMed search

[1]

[2]

Hepatocyte nuclear factor 4 alpha (HNF4A) also known as NR2A1 (nuclear receptor subfamily 2, group A, member 1) is a nuclear receptor that in humans is encoded by the HNF4A gene.^[1]^[2]

1 Function
2 Clinical significance
3 Interactions
4 See also
5 References
6 Further reading
7 External links

Function

HNF-4α is a nuclear transcription factor that binds DNA as a homodimer. The encoded protein controls the expression of several genes, including hepatocyte nuclear factor 1 alpha, a transcription factor which regulates the expression of several hepatic genes. This gene plays a role in development of the liver , kidney , and intestines . Alternative splicing of this gene results in multiple transcript variants.^[3]

HNF4A is required for the PXR and CAR-mediated transcriptional activation of CYP3A4.^[4]

The alkaloid berberine upregulates the expression of HNF4A.^[5]

Clinical significance

Mutations in this gene have been associated with monogenic autosomal dominant non-insulin-dependent diabetes mellitus type II.^[3]

Interactions

Hepatocyte nuclear factor 4 alpha has been shown to interact with:

References

^ Chartier FL, Bossu JP, Laudet V, Fruchart JC, Laine B (September 1994). "Cloning and sequencing of cDNAs encoding the human hepatocyte nuclear factor 4 indicate the presence of two isoforms in human liver". Gene 147 (2): 269–72. doi:10.1016/0378-1119(94)90079-5. PMID 7926813.
^ Argyrokastritis A, Kamakari S, Kapsetaki M, Kritis A, Talianidis I, Moschonas NK (February 1997). "Human hepatocyte nuclear factor-4 (hHNF-4) gene maps to 20q12-q13.1 between PLCG1 and D20S17". Hum. Genet. 99 (2): 233–6. doi:10.1007/s004390050345. PMID 9048927.
^ ^a ^b "Entrez Gene: HNF4A hepatocyte nuclear factor 4, alpha". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3172.
^ Tirona RG, Lee W, Leake BF, Lan LB, Cline CB, Lamba V, Parviz F, Duncan SA, Inoue Y, Gonzalez FJ, Schuetz EG, Kim RB (February 2003). "The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4". Nat. Med. 9 (2): 220–4. doi:10.1038/nm815. PMID 12514743.
^ Wang ZQ, Lu FE, Leng SH, Fang XS, Chen G, Wang ZS, Dong LP, Yan ZQ (October 2008). "Facilitating effects of berberine on rat pancreatic islets through modulating hepatic nuclear factor 4 alpha expression and glucokinase activity". World J. Gastroenterol. 14 (39): 6004–11. doi:10.3748/wjg.14.6004. PMC 2760199. PMID 18932278. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2760199.
^ Mulholland DJ, Read JT, Rennie PS, Cox ME, Nelson CC (August 2003). "Functional localization and competition between the androgen receptor and T-cell factor for nuclear beta-catenin: a means for inhibition of the Tcf signaling axis". Oncogene 22 (36): 5602–13. doi:10.1038/sj.onc.1206802. PMID 12944908.
^ Yoshida E, Aratani S, Itou H, Miyagishi M, Takiguchi M, Osumu T, Murakami K, Fukamizu A (December 1997). "Functional association between CBP and HNF4 in trans-activation". Biochem. Biophys. Res. Commun. 241 (3): 664–9. doi:10.1006/bbrc.1997.7871. PMID 9434765.
^ Dell H, Hadzopoulou-Cladaras M (March 1999). "CREB-binding protein is a transcriptional coactivator for hepatocyte nuclear factor-4 and enhances apolipoprotein gene expression". J. Biol. Chem. 274 (13): 9013–21. doi:10.1074/jbc.274.13.9013. PMID 10085149.
^ ^a ^b Maeda Y, Rachez C, Hawel L, Byus CV, Freedman LP, Sladek FM (July 2002). "Polyamines modulate the interaction between nuclear receptors and vitamin D receptor-interacting protein 205". Mol. Endocrinol. 16 (7): 1502–10. doi:10.1210/me.16.7.1502. PMID 12089346.
^ ^a ^b Malik S, Wallberg AE, Kang YK, Roeder RG (August 2002). "TRAP/SMCC/Mediator-Dependent Transcriptional Activation from DNA and Chromatin Templates by Orphan Nuclear Receptor Hepatocyte Nuclear Factor 4". Mol. Cell. Biol. 22 (15): 5626–37. doi:10.1128/MCB.22.15.5626-5637.2002. PMC 133960. PMID 12101254. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=133960.
^ Lee YK, Dell H, Dowhan DH, Hadzopoulou-Cladaras M, Moore DD (January 2000). "The Orphan Nuclear Receptor SHP Inhibits Hepatocyte Nuclear Factor 4 and Retinoid X Receptor Transactivation: Two Mechanisms for Repression". Mol. Cell. Biol. 20 (1): 187–95. doi:10.1128/MCB.20.1.187-195.2000. PMC 85074. PMID 10594021. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=85074.
^ Lin WJ, Li J, Lee YF, Yeh SD, Altuwaijri S, Ou JH, Chang C (March 2003). "Suppression of hepatitis B virus core promoter by the nuclear orphan receptor TR4". J. Biol. Chem. 278 (11): 9353–60. doi:10.1074/jbc.M205944200. PMID 12522137.

External links

FactorBook HNF4A

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

PDB gallery

1m7w: HNF4a ligand binding domain with bound fatty acid

1pzl: Crystal structure of HNF4a LBD in complex with the ligand and the coactivator SRC-1 peptide

Transcription factors and intracellular receptors

(1) Basic domains

(1.1) Basic leucine zipper (bZIP)	Activating transcription factor (AATF, 1, 2, 3, 4, 5, 6, 7) · AP-1 (c-Fos, FOSB, FOSL1, FOSL2, JDP2, c-Jun, JUNB, JUND) · BACH (1, 2) · BATF · BLZF1 · C/EBP (α, β, γ, δ, ε, ζ) · CREB (1, 3, L1) · CREM · DBP · DDIT3 · GABPA · HLF · MAF (B, F, G, K) · NFE (2, L1, L2, L3) · NFIL3 · NRL · NRF (1, 2, 3) · XBP1

(1.2) Basic helix-loop-helix (bHLH)	ATOH1 · AhR · AHRR · ARNT · ASCL1 · BHLHB2 · BMAL (ARNTL, ARNTL2) · CLOCK · EPAS1 · FIGLA · HAND (1, 2) · HES (5, 6) · HEY (1, 2, L) · HES1 · HIF (1A, 3A) · ID (1, 2, 3, 4) · LYL1 · MESP2 · MXD4 · MYCL1 · MYCN · Myogenic regulatory factors (MyoD, Myogenin, MYF5, MYF6) · Neurogenins (1, 2, 3) · NeuroD (1, 2) · NPAS (1, 2, 3) · OLIG (1, 2) · Pho4 · Scleraxis · SIM (1, 2) · TAL (1, 2) · Twist · USF1

(1.3) bHLH-ZIP	AP-4 · MAX · MITF · MNT · MLX · MXI1 · Myc · SREBP (1, 2)

(1.4) NF-1	NFI (A, B, C, X) · SMAD (R-SMAD (1, 2, 3, 5, 9) - I-SMAD (6, 7) - 4)

(1.5) RF-X	RFX (1, 2, 3, 4, 5, ANK)

(1.6) Basic helix-span-helix (bHSH)	AP-2 (α, β, γ, δ, ε)

(2) Zinc finger DNA-binding domains

(2.1) Nuclear receptor (Cys₄)	subfamily 1 (Thyroid hormone (α, β), CAR, FXR, LXR (α, β), PPAR (α, β/δ, γ), PXR, RAR (α, β, γ), ROR (α, β, γ), Rev-ErbA (α, β), VDR) subfamily 2 (COUP-TF (I, II), Ear-2, HNF4 (α, γ), PNR, RXR (α, β, γ), Testicular receptor (2, 4), TLX) subfamily 3 (Steroid hormone (Androgen, Estrogen (α, β), Glucocorticoid, Mineralocorticoid, Progesterone), Estrogen related (α, β, γ)) subfamily 4 NUR (NGFIB, NOR1, NURR1) · subfamily 5 (LRH-1, SF1) · subfamily 6 (GCNF) · subfamily 0 (DAX1, SHP)

(2.2) Other Cys₄	GATA (1, 2, 3, 4, 5, 6) · MTA (1, 2, 3) · TRPS1

(2.3) Cys₂His₂	General transcription factors (TFIIA, TFIIB, TFIID, TFIIE (1, 2), TFIIF (1, 2), TFIIH (1, 2, 4, 2I, 3A, 3C1, 3C2)) ATBF1 · BCL (6, 11A, 11B) · CTCF · E4F1 · EGR (1, 2, 3, 4) · ERV3 · GFI1 · GLI-Krüppel family (1, 2, 3, REST, S2, YY1) · HIC (1, 2) · HIVEP (1, 2, 3) · IKZF (1, 2, 3) · ILF (2, 3) · KLF (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17) · MTF1 · MYT1 · OSR1 · PRDM9 · SALL (1, 2, 3, 4) · SP (1, 2, 4, 7, 8) · TSHZ3 · WT1 · Zbtb7 (7A, 7B) · ZBTB (16, 17, 20, 32, 33, 40) · zinc finger (3, 7, 9, 10, 19, 22, 24, 33B, 34, 35, 41, 43, 44, 51, 74, 143, 146, 148, 165, 202, 217, 219, 238, 239, 259, 267, 268, 281, 295, 300, 318, 330, 346, 350, 365, 366, 384, 423, 451, 452, 471, 593, 638, 644, 649, 655)

(2.4) Cys₆	HIVEP1

(2.5) Alternating composition	AIRE · DIDO1 · GRLF1 · ING (1, 2, 4) · JARID (1A, 1B, 1C, 1D, 2) · JMJD1B

(3) Helix-turn-helix domains

(3.1) Homeodomain	ARX · CDX (1, 2) · CRX · CUTL1 · DBX (1, 2) · DLX (3, 4, 5) · EMX2 · EN (1, 2) · FHL (1, 2, 3) · HESX1 · HHEX · HLX · Homeobox (A1, A2, A3, A4, A5, A7, A9, A10, A11, A13, B1, B2, B3, B4, B5, B6, B7, B8, B9, B13, C4, C5, C6, C8, C9, C10, C11, C12, C13, D1, D3, D4, D8, D9, D10, D11, D12, D13) · HOPX · IRX (1, 2, 3, 4, 5, 6, MKX) · LMX (1A, 1B) · MEIS (1, 2) · MEOX2 · MNX1 · MSX (1, 2) · NANOG · NKX (2-1, 2-2, 2-3, 2-5, 3-1, 3-2, 6-1, 6-2) · NOBOX · PBX (1, 2, 3) · PHF (1, 3, 6, 8, 10, 16, 17, 20, 21A) · PHOX (2A, 2B) · PITX (1, 2, 3) · POU domain (PIT-1, BRN-3: A, B, C, Octamer transcription factor: 1, 2, 3/4, 6, 7, 11) · OTX (1, 2) · PDX1 · SATB2 · SHOX2 · VAX1 · ZEB (1, 2)

(3.2) Paired box	PAX (1, 2, 3, 4, 5, 6, 7, 8, 9)

(3.3) Fork head / winged helix	E2F (1, 2, 3, 4, 5) · FOX proteins (A1, A2, A3, C1, C2, D3, D4, E1, E3, F1, G1, H1, I1, J1, J2, K1, K2, L2, M1, N1, N3, O1, O3, O4, P1, P2, P3, P4)

(3.4) Heat Shock Factors	HSF (1, 2, 4)

(3.5) Tryptophan clusters	ELF (2, 4, 5) · EGF · ELK (1, 3, 4) · ERF · ETS (1, 2, ERG, SPIB) · ETV (1, 4, 5, 6) · FLI1 · Interferon regulatory factors (1, 2, 3, 4, 5, 6, 7, 8) · MYB · MYBL2

(3.6) TEA domain	transcriptional enhancer factor (1, 2, 3, 4)

(4) β-Scaffold factors with minor groove contacts

(4.1) Rel homology region	NF-κB (NFKB1, NFKB2, REL, RELA, RELB) · NFAT (C1, C2, C3, C4, 5)

(4.2) STAT	STAT (1, 2, 3, 4, 5, 6)

(4.3) p53	p53 · TBX (1, 2, 3, 5, 19, 21, 22, Brachyury, TBR1, TBR2) · TP63

(4.4) MADS box	Mef2 (A, B, C, D) · SRF

(4.6) TATA binding proteins	TBP · TBPL1

(4.7) High-mobility group	BBX · HMGB (1, 2, 3, 4) · HMGN (1, 2, 3, 4) · HNF (1A, 1B) · LEF1 · SOX (1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 18, 21) · SRY · SSRP1 · TCF (3, 4) · TOX (1, 2, 3, 4)

(4.10) Cold-shock domain	CSDA, YBX1

(4.11) Runt	CBF (CBFA2T2, CBFA2T3, RUNX1, RUNX2, RUNX3, RUNX1T1)

(0) Other transcription factors

(0.2) HMGI(Y)	HMGA (1, 2) · HBP1

(0.3) Pocket domain	Rb · RBL1 · RBL2

(0.5) AP-2/EREBP-related factors	Apetala 2 · EREBP · B3

(0.6) Miscellaneous	ARID (1A, 1B, 2, 3A, 3B, 4A) · CAP · IFI (16, 35) · MLL (2, 3, T1) · MNDA · NFY (A, B, C) · Rho/Sigma

see also transcription factor/coregulator deficiencies
B bsyn: dna (repl, cycl, reco, repr) · tscr (fact, tcrg, nucl, rnat, rept, ptts) · tltn (risu, pttl, nexn) · dnab, rnab/runp · stru (domn, 1°, 2°, 3°, 4°)

Hepatocyte nuclear factor 4 alpha

Contents

Function

Clinical significance

Interactions

See also

References

Further reading

External links