HNF4A

HNF4A
PDBに登録されている構造
PDB	オルソログ検索: RCSB PDBe PDBj
PDBのIDコード一覧
	1PZL, 3CBB, 3FS1, 4B7W, 4IQR
識別子
記号	HNF4A, HNF4, HNF4a7, HNF4a8, HNF4a9, HNF4alpha, MODY, MODY1, NR2A1, NR2A21, TCF, TCF14, FRTS4, Hepatocyte nuclear factor 4 alpha, TCF-14
外部ID	OMIM: 600281 MGI: 109128 HomoloGene: 395 GeneCards: HNF4A
遺伝子の位置 (ヒト)
染色体	20番染色体 (ヒト)
終点	44,432,845 bp
遺伝子の位置 (マウス)
染色体	2番染色体 (マウス)
終点	163,414,830 bp
RNA発現パターン
	; ; ; ;
	さらなる参照発現データ
遺伝子オントロジー
分子機能	• DNA結合; • sequence-specific DNA binding; • DNA-binding transcription factor activity; • DNA-binding transcription activator activity, RNA polymerase II-specific; • zinc ion binding; • 金属イオン結合; • steroid hormone receptor activity; • nuclear receptor activity; • 血漿タンパク結合; • transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding; • 受容体結合; • fatty acid binding; • protein homodimerization activity; • RNA polymerase II cis-regulatory region sequence-specific DNA binding; • DNA-binding transcription factor activity, RNA polymerase II-specific;
細胞の構成要素	• 細胞核; • 細胞質; • 核質;
生物学的プロセス	• triglyceride homeostasis; • ornithine metabolic process; • phospholipid homeostasis; • regulation of transcription, DNA-templated; • SMAD protein signal transduction; • glucose homeostasis; • regulation of insulin secretion; • 脂質代謝; • regulation of transcription by RNA polymerase II; • signal transduction involved in regulation of gene expression; • sex differentiation; • 凝固・線溶系; • response to glucose; • transcription, DNA-templated; • positive regulation of transcription, DNA-templated; • regulation of lipid metabolic process; • intracellular receptor signaling pathway; • regulation of growth hormone receptor signaling pathway; • negative regulation of cell growth; • lipid homeostasis; • 生体異物の代謝プロセス; • transcription initiation from RNA polymerase II promoter; • regulation of gastrulation; • steroid hormone mediated signaling pathway; • positive regulation of transcription by RNA polymerase II; • negative regulation of cell population proliferation; • cholesterol homeostasis; • type B pancreatic cell development; • hepatocyte differentiation; • regulation of circadian rhythm; • negative regulation of transcription, DNA-templated; • 周期的プロセス;
	出典:Amigo / QuickGO
オルソログ
	3172
	15378
	ENSG00000101076
	ENSMUSG00000017950
	P41235
	P49698
NM_000457; NM_001030003; NM_001030004; NM_001258355; NM_001287182;
	NM_001287183; NM_001287184; NM_175914; NM_178849; NM_178850
	NM_008261; NM_001312906; NM_001312907
NP_000448; NP_001025174; NP_001025175; NP_001245284; NP_001274111;
	NP_001274112; NP_001274113; NP_787110; NP_849180; NP_849181
	NP_001299835; NP_001299836; NP_032287
	ウィキデータ
閲覧/編集ヒト	閲覧/編集マウス

HNF4AまたはHNF4α（hepatocyte nuclear factor 4 alpha）、NR2A1（nuclear receptor subfamily 2, group A, member 1）は、ヒトではHNF4A遺伝子にコードされる核内受容体である^[5]^[6]。

機能[編集]

HNF4αはホモ二量体としてDNAに結合する転写因子であり、肝臓遺伝子の発現を調節する転写因子であるHNF1αなど、いくつかの遺伝子の発現を制御する。HNF4αは肝臓、腎臓、腸の発生に関与している。HNF4A遺伝子からは選択的スプライシングにより、複数の転写バリアントが生じる^[7]。

HNF4AはPXRとCAR（英語版）を介したCYP3A4の転写活性化に必要である^[8]。HNF4A遺伝子の変異は、CYP2D6などHNF4αの下流のタンパク質の活性に影響を与える^[9]^[10]。

アルカロイドの1種であるベルベリンは、HNF4Aの発現をアップレギュレーションする。

臨床的意義[編集]

HNF4A遺伝子の変異は、若年発症成人型糖尿病（英語版）（MODY）^[11]、特にMODY 1（英語版）と関係している。少なくとも56種類の疾患原因変異がこの遺伝子には発見されている^[12]。

大腸がんではHNF4αの増幅が観察される^[13]。

HNF4A遺伝子のミスセンス変異は、ファンコーニ症候群の表現型の出現とも関係している^[14]。

相互作用[編集]

HNF4αは次に挙げる因子と相互作用することが示されている。

出典[編集]

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000101076 - Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000017950 - Ensembl, May 2017
^ Human PubMed Reference:
^ Mouse PubMed Reference:
^ “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. (Sep 1994). doi:10.1016/0378-1119(94)90079-5. PMID 7926813.
^ “Human hepatocyte nuclear factor-4 (hHNF-4) gene maps to 20q12-q13.1 between PLCG1 and D20S17”. Human Genetics 99 (2): 233–6. (Feb 1997). doi:10.1007/s004390050345. PMID 9048927.
^ “Entrez Gene: HNF4A hepatocyte nuclear factor 4, alpha”. 2023年6月7日閲覧。
^ “The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4”. Nature Medicine 9 (2): 220–4. (Feb 2003). doi:10.1038/nm815. PMID 12514743.
^ “Genetic polymorphism of hepatocyte nuclear factor-4alpha influences human cytochrome P450 2D6 activity”. Hepatology 48 (2): 635–45. (2008). doi:10.1002/hep.22396. PMID 18666237.
^ “Effect of HNF4α genetic polymorphism G60D on the pharmacokinetics of CYP2D6 substrate tolterodine in healthy Korean individuals”. Pharmacogenetics and Genomics 23 (3): 175–9. (2013). doi:10.1097/FPC.0b013e32835de25e. PMID 23292115.
^ “Roles of HNF1α and HNF4α in pancreatic β-cells: lessons from a monogenic form of diabetes (MODY)”. Vitamins and Hormones 95: 407–23. (2014). doi:10.1016/B978-0-12-800174-5.00016-8. PMID 24559927.
^ “Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases”. Scientific Reports 9 (1): 18577. (December 2019). Bibcode: 2019NatSR...918577S. doi:10.1038/s41598-019-54976-4. PMC 6901466. PMID 31819097.
^ “Proteogenomic characterization of human colon and rectal cancer”. Nature 513 (7518): 382–7. (2014). Bibcode: 2014Natur.513..382.. doi:10.1038/nature13438. PMC 4249766. PMID 25043054.
^ “Proximal renal tubular acidosis with and without Fanconi syndrome”. Kidney Research and Clinical Practice 38 (3): 267–281. (September 2019). doi:10.23876/j.krcp.19.056. PMC 6727890. PMID 31474092.
^ “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. (Aug 2003). doi:10.1038/sj.onc.1206802. PMID 12944908.
^ “Functional association between CBP and HNF4 in trans-activation”. Biochemical and Biophysical Research Communications 241 (3): 664–9. (Dec 1997). doi:10.1006/bbrc.1997.7871. PMID 9434765.
^ “CREB-binding protein is a transcriptional coactivator for hepatocyte nuclear factor-4 and enhances apolipoprotein gene expression”. The Journal of Biological Chemistry 274 (13): 9013–21. (Mar 1999). doi:10.1074/jbc.274.13.9013. PMID 10085149.
^ ^a ^b “Polyamines modulate the interaction between nuclear receptors and vitamin D receptor-interacting protein 205”. Molecular Endocrinology 16 (7): 1502–10. (Jul 2002). doi:10.1210/mend.16.7.0883. PMID 12089346.
^ ^a ^b “TRAP/SMCC/mediator-dependent transcriptional activation from DNA and chromatin templates by orphan nuclear receptor hepatocyte nuclear factor 4”. Molecular and Cellular Biology 22 (15): 5626–37. (Aug 2002). doi:10.1128/MCB.22.15.5626-5637.2002. PMC 133960. PMID 12101254.
^ “The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: two mechanisms for repression”. Molecular and Cellular Biology 20 (1): 187–95. (Jan 2000). doi:10.1128/MCB.20.1.187-195.2000. PMC 85074. PMID 10594021.
^ “Suppression of hepatitis B virus core promoter by the nuclear orphan receptor TR4”. The Journal of Biological Chemistry 278 (11): 9353–60. (Mar 2003). doi:10.1074/jbc.M205944200. PMID 12522137.

外部リンク[編集]

FactorBook HNF4A

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000101076 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000017950 - Ensembl, May 2017

[3] Human PubMed Reference:

[4] Mouse PubMed Reference:

[pmid7926813-5] “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. (Sep 1994). doi:10.1016/0378-1119(94)90079-5. PMID 7926813.

[pmid9048927-6] “Human hepatocyte nuclear factor-4 (hHNF-4) gene maps to 20q12-q13.1 between PLCG1 and D20S17”. Human Genetics 99 (2): 233–6. (Feb 1997). doi:10.1007/s004390050345. PMID 9048927.

[entrez-7] “Entrez Gene: HNF4A hepatocyte nuclear factor 4, alpha”. 2023年6月7日閲覧。

[pmid12514743-8] “The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4”. Nature Medicine 9 (2): 220–4. (Feb 2003). doi:10.1038/nm815. PMID 12514743.

[pmid18666237-9] “Genetic polymorphism of hepatocyte nuclear factor-4alpha influences human cytochrome P450 2D6 activity”. Hepatology 48 (2): 635–45. (2008). doi:10.1002/hep.22396. PMID 18666237.

[pmid23292115-10] “Effect of HNF4α genetic polymorphism G60D on the pharmacokinetics of CYP2D6 substrate tolterodine in healthy Korean individuals”. Pharmacogenetics and Genomics 23 (3): 175–9. (2013). doi:10.1097/FPC.0b013e32835de25e. PMID 23292115.

[pmid24559927-11] “Roles of HNF1α and HNF4α in pancreatic β-cells: lessons from a monogenic form of diabetes (MODY)”. Vitamins and Hormones 95: 407–23. (2014). doi:10.1016/B978-0-12-800174-5.00016-8. PMID 24559927.

[Šimčíková_2019_-_supplementary_table_S7-12] “Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases”. Scientific Reports 9 (1): 18577. (December 2019). Bibcode: 2019NatSR...918577S. doi:10.1038/s41598-019-54976-4. PMC 6901466. PMID 31819097.

[pmid25043054-13] “Proteogenomic characterization of human colon and rectal cancer”. Nature 513 (7518): 382–7. (2014). Bibcode: 2014Natur.513..382.. doi:10.1038/nature13438. PMC 4249766. PMID 25043054.

[pmid31474092-14] “Proximal renal tubular acidosis with and without Fanconi syndrome”. Kidney Research and Clinical Practice 38 (3): 267–281. (September 2019). doi:10.23876/j.krcp.19.056. PMC 6727890. PMID 31474092.

[pmid12944908-15] “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. (Aug 2003). doi:10.1038/sj.onc.1206802. PMID 12944908.

[pmid9434765-16] “Functional association between CBP and HNF4 in trans-activation”. Biochemical and Biophysical Research Communications 241 (3): 664–9. (Dec 1997). doi:10.1006/bbrc.1997.7871. PMID 9434765.

[pmid10085149-17] “CREB-binding protein is a transcriptional coactivator for hepatocyte nuclear factor-4 and enhances apolipoprotein gene expression”. The Journal of Biological Chemistry 274 (13): 9013–21. (Mar 1999). doi:10.1074/jbc.274.13.9013. PMID 10085149.

[pmid12089346-18] “Polyamines modulate the interaction between nuclear receptors and vitamin D receptor-interacting protein 205”. Molecular Endocrinology 16 (7): 1502–10. (Jul 2002). doi:10.1210/mend.16.7.0883. PMID 12089346.

[pmid12101254-19] “TRAP/SMCC/mediator-dependent transcriptional activation from DNA and chromatin templates by orphan nuclear receptor hepatocyte nuclear factor 4”. Molecular and Cellular Biology 22 (15): 5626–37. (Aug 2002). doi:10.1128/MCB.22.15.5626-5637.2002. PMC 133960. PMID 12101254.

[pmid10594021-20] “The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: two mechanisms for repression”. Molecular and Cellular Biology 20 (1): 187–95. (Jan 2000). doi:10.1128/MCB.20.1.187-195.2000. PMC 85074. PMID 10594021.

[pmid12522137-21] “Suppression of hepatitis B virus core promoter by the nuclear orphan receptor TR4”. The Journal of Biological Chemistry 278 (11): 9353–60. (Mar 2003). doi:10.1074/jbc.M205944200. PMID 12522137.

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