FOXA1_MOUSE
ID FOXA1_MOUSE Reviewed; 468 AA.
AC P35582; Q4VA63; Q61108;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1997, sequence version 2.
DT 03-AUG-2022, entry version 189.
DE RecName: Full=Hepatocyte nuclear factor 3-alpha;
DE Short=HNF-3-alpha;
DE Short=HNF-3A;
DE AltName: Full=Forkhead box protein A1;
GN Name=Foxa1; Synonyms=Hnf3a, Tcf-3a, Tcf3a;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=8034310; DOI=10.1006/geno.1994.1191;
RA Kaestner K., Hiemisch H., Luckow B., Schuetz G.;
RT "The HNF-3 gene family of transcription factors in mice: gene structure,
RT cDNA sequence, and mRNA distribution.";
RL Genomics 20:377-385(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Farrington S.M., Baron M.H.;
RL Submitted (JAN-1996) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP DISRUPTION PHENOTYPE, AND FUNCTION IN GLUCOSE HOMEOSTASIS.
RX PubMed=10049364; DOI=10.1101/gad.13.4.495;
RA Kaestner K.H., Katz J., Liu Y., Drucker D.J., Schutz G.;
RT "Inactivation of the winged helix transcription factor HNF3alpha affects
RT glucose homeostasis and islet glucagon gene expression in vivo.";
RL Genes Dev. 13:495-504(1999).
RN [5]
RP ASSOCIATION WITH NUCLEOSOMES.
RX PubMed=11571307; DOI=10.1074/jbc.m108214200;
RA Chaya D., Hayamizu T., Bustin M., Zaret K.S.;
RT "Transcription factor FoxA (HNF3) on a nucleosome at an enhancer complex in
RT liver chromatin.";
RL J. Biol. Chem. 276:44385-44389(2001).
RN [6]
RP FUNCTION IN CHROMATIN OPENING, AND INTERACTION WITH HISTONES H3 AND H4.
RX PubMed=11864602; DOI=10.1016/s1097-2765(02)00459-8;
RA Cirillo L.A., Lin F.R., Cuesta I., Friedman D., Jarnik M., Zaret K.S.;
RT "Opening of compacted chromatin by early developmental transcription
RT factors HNF3 (FoxA) and GATA-4.";
RL Mol. Cell 9:279-289(2002).
RN [7]
RP DISRUPTION PHENOTYPE.
RX PubMed=15252040; DOI=10.1074/jbc.m403354200;
RA Behr R., Brestelli J., Fulmer J.T., Miyawaki N., Kleyman T.R.,
RA Kaestner K.H.;
RT "Mild nephrogenic diabetes insipidus caused by Foxa1 deficiency.";
RL J. Biol. Chem. 279:41936-41941(2004).
RN [8]
RP FUNCTION IN PROSTATE DEVELOPMENT, SUBCELLULAR LOCATION, TISSUE SPECIFICITY,
RP AND DISRUPTION PHENOTYPE.
RX PubMed=15987773; DOI=10.1242/dev.01917;
RA Gao N., Ishii K., Mirosevich J., Kuwajima S., Oppenheimer S.R.,
RA Roberts R.L., Jiang M., Yu X., Shappell S.B., Caprioli R.M., Stoffel M.,
RA Hayward S.W., Matusik R.J.;
RT "Forkhead box A1 regulates prostate ductal morphogenesis and promotes
RT epithelial cell maturation.";
RL Development 132:3431-3443(2005).
RN [9]
RP FUNCTION IN CHROMATIN OPENING.
RX PubMed=15748903; DOI=10.1016/j.yexcr.2004.12.002;
RA Holmqvist P.H., Belikov S., Zaret K.S., Wrange O.;
RT "FoxA1 binding to the MMTV LTR modulates chromatin structure and
RT transcription.";
RL Exp. Cell Res. 304:593-603(2005).
RN [10]
RP FUNCTION IN LUNG DEVELOPMENT.
RX PubMed=15668254; DOI=10.1074/jbc.m414122200;
RA Wan H., Dingle S., Xu Y., Besnard V., Kaestner K.H., Ang S.L., Wert S.,
RA Stahlman M.T., Whitsett J.A.;
RT "Compensatory roles of Foxa1 and Foxa2 during lung morphogenesis.";
RL J. Biol. Chem. 280:13809-13816(2005).
RN [11]
RP FUNCTION IN LIVER DEVELOPMENT.
RX PubMed=15959514; DOI=10.1038/nature03649;
RA Lee C.S., Friedman J.R., Fulmer J.T., Kaestner K.H.;
RT "The initiation of liver development is dependent on Foxa transcription
RT factors.";
RL Nature 435:944-947(2005).
RN [12]
RP FUNCTION IN NEURON DEVELOPMENT.
RX PubMed=17596284; DOI=10.1242/dev.000141;
RA Ferri A.L., Lin W., Mavromatakis Y.E., Wang J.C., Sasaki H., Whitsett J.A.,
RA Ang S.L.;
RT "Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron
RT development in a dosage-dependent manner.";
RL Development 134:2761-2769(2007).
RN [13]
RP DEVELOPMENTAL STAGE.
RX PubMed=17220277; DOI=10.1128/mcb.01133-06;
RA Minoo P., Hu L., Xing Y., Zhu N.L., Chen H., Li M., Borok Z., Li C.;
RT "Physical and functional interactions between homeodomain NKX2.1 and winged
RT helix/forkhead FOXA1 in lung epithelial cells.";
RL Mol. Cell. Biol. 27:2155-2165(2007).
RN [14]
RP FUNCTION IN PANCREAS DEVELOPMENT.
RX PubMed=19141476; DOI=10.1101/gad.1752608;
RA Gao N., LeLay J., Vatamaniuk M.Z., Rieck S., Friedman J.R., Kaestner K.H.;
RT "Dynamic regulation of Pdx1 enhancers by Foxa1 and Foxa2 is essential for
RT pancreas development.";
RL Genes Dev. 22:3435-3448(2008).
RN [15]
RP FUNCTION IN BILE DUCT DEVELOPMENT.
RX PubMed=19436110; DOI=10.1172/jci38201;
RA Li Z., White P., Tuteja G., Rubins N., Sackett S., Kaestner K.H.;
RT "Foxa1 and Foxa2 regulate bile duct development in mice.";
RL J. Clin. Invest. 119:1537-1545(2009).
CC -!- FUNCTION: Transcription factor that is involved in embryonic
CC development, establishment of tissue-specific gene expression and
CC regulation of gene expression in differentiated tissues. Is thought to
CC act as a 'pioneer' factor opening the compacted chromatin for other
CC proteins through interactions with nucleosomal core histones and
CC thereby replacing linker histones at target enhancer and/or promoter
CC sites. Binds DNA with the consensus sequence 5'-
CC [AC]A[AT]T[AG]TT[GT][AG][CT]T[CT]-3' (By similarity). Proposed to play
CC a role in translating the epigenetic signatures into cell type-specific
CC enhancer-driven transcriptional programs. Involved in the development
CC of multiple endoderm-derived organ systems such as the liver, pancreas,
CC lungs and prostate; FOXA1 and FOXA2 seem to have at least in part
CC redundant roles. Plays a role in prostate morphogenesis and epithelial
CC cell differentiation. FOXA1 and FOXA2 are essential for hepatic
CC specification. FOXA1 and FOXA2 are required for morphogenesis and cell
CC differentiation during formation of the lung. FOXA1 and FOXA2 are
CC involved in bile duct formation; they positively regulate the binding
CC of glucocorticoid receptor/NR3C1 to the IL6 promoter. FOXA1 and FOXA2
CC regulate multiple phases of midbrain dopaminergic neuron development;
CC they regulate expression of NEUROG2 at the beginning of mDA
CC neurogenesis and of NR4A2 and EN1 in immature mDA neurons. Modulates
CC the transcriptional activity of nuclear hormone receptors. Is involved
CC in ESR1-mediated transcription. Inhibits NKX2-1-mediated transcription
CC from the SFTPC promoter in lung epithel independently from DNA-binding.
CC Involved in regulation of apoptosis. Involved in cell cycle regulation.
CC Originally described as a transcription activator for a number of liver
CC genes such as AFP, albumin, tyrosine aminotransferase, PEPCK, etc.
CC Interacts with the cis-acting regulatory regions of these genes.
CC Involved in glucose homeostasis; activates the GCG promoter.
CC {ECO:0000250, ECO:0000269|PubMed:10049364, ECO:0000269|PubMed:11864602,
CC ECO:0000269|PubMed:15668254, ECO:0000269|PubMed:15748903,
CC ECO:0000269|PubMed:15959514, ECO:0000269|PubMed:15987773,
CC ECO:0000269|PubMed:17596284, ECO:0000269|PubMed:19141476,
CC ECO:0000269|PubMed:19436110}.
CC -!- SUBUNIT: Binds DNA as a monomer. Interacts with FOXA2. Interacts with
CC NKX2-1. Interacts with HDAC7. Interacts with the histone H3-H4
CC heterodimer. Associates with nucleosomes containing histone H2A.
CC Interacts with AR. Interacts with NR0B2 (By similarity). {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00089,
CC ECO:0000269|PubMed:15987773}.
CC -!- TISSUE SPECIFICITY: Restricted mainly to endoderm-derived tissues
CC (lung, liver, stomach, and small intestine). Expressed in the prostate.
CC {ECO:0000269|PubMed:15987773}.
CC -!- DEVELOPMENTAL STAGE: Most abundant in midgestation embryos (day 9.5).
CC In embryonic lung expressed at 12 dpc and 18 dpc with highest levels in
CC proximal airways and lowest levels in the distal lung.
CC {ECO:0000269|PubMed:17220277}.
CC -!- DISRUPTION PHENOTYPE: The prostate shows a severely altered ductal
CC pattern that resembles primitive epithelial cords surrounded by thick
CC stromal layers; no differentiated or mature luminal epithelial cells
CC are found. Dehydration and electrolyte imbalance, development of mild
CC nephrogenic diabetes insipidus. Severe hypoglycemia due to at least in
CC part diminished expression of GCG. Mice deficient for Fox1a and
CC deficient for Foxa2 in the endoderm from 8.5 dpc onwards do not show
CC hepatic bud formation. Mice deficient for Fox1a and deficient for Foxa2
CC in the midbrain from 10.5 dpc onwards show almost complete loss of mDA
CC neurons. Mice deficient for Fox1a and deficient for Foxa2 in the
CC embryonic liver show hyperplasia of the biliary tree due to at least in
CC part activation of IL-6 expression, a proliferative signal for
CC cholangiocytes. {ECO:0000269|PubMed:10049364,
CC ECO:0000269|PubMed:15252040, ECO:0000269|PubMed:15987773}.
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DR EMBL; X74936; CAA52890.1; -; mRNA.
DR EMBL; U44752; AAA86760.1; -; mRNA.
DR EMBL; BC096524; AAH96524.1; -; mRNA.
DR CCDS; CCDS25926.1; -.
DR PIR; A54258; A54258.
DR RefSeq; NP_032285.2; NM_008259.3.
DR RefSeq; XP_006515542.1; XM_006515479.3.
DR RefSeq; XP_006515544.1; XM_006515481.2.
DR RefSeq; XP_006515546.1; XM_006515483.1.
DR RefSeq; XP_017170451.1; XM_017314962.1.
DR AlphaFoldDB; P35582; -.
DR SMR; P35582; -.
DR BioGRID; 200351; 2.
DR IntAct; P35582; 2.
DR STRING; 10090.ENSMUSP00000041118; -.
DR iPTMnet; P35582; -.
DR PhosphoSitePlus; P35582; -.
DR MaxQB; P35582; -.
DR PaxDb; P35582; -.
DR PeptideAtlas; P35582; -.
DR PRIDE; P35582; -.
DR ProteomicsDB; 267396; -.
DR Antibodypedia; 23304; 1476 antibodies from 43 providers.
DR DNASU; 15375; -.
DR Ensembl; ENSMUST00000044380; ENSMUSP00000041118; ENSMUSG00000035451.
DR GeneID; 15375; -.
DR KEGG; mmu:15375; -.
DR UCSC; uc007nps.1; mouse.
DR CTD; 3169; -.
DR MGI; MGI:1347472; Foxa1.
DR VEuPathDB; HostDB:ENSMUSG00000035451; -.
DR eggNOG; KOG3563; Eukaryota.
DR GeneTree; ENSGT00940000162043; -.
DR HOGENOM; CLU_027910_4_1_1; -.
DR InParanoid; P35582; -.
DR OMA; FKCEKQA; -.
DR OrthoDB; 1181467at2759; -.
DR PhylomeDB; P35582; -.
DR TreeFam; TF316127; -.
DR Reactome; R-MMU-9018519; Estrogen-dependent gene expression.
DR BioGRID-ORCS; 15375; 2 hits in 74 CRISPR screens.
DR ChiTaRS; Foxa1; mouse.
DR PRO; PR:P35582; -.
DR Proteomes; UP000000589; Chromosome 12.
DR RNAct; P35582; protein.
DR Bgee; ENSMUSG00000035451; Expressed in prostate gland ventral lobe and 157 other tissues.
DR Genevisible; P35582; MM.
DR GO; GO:0001650; C:fibrillar center; ISO:MGI.
DR GO; GO:0005902; C:microvillus; IDA:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0003682; F:chromatin binding; IDA:MGI.
DR GO; GO:0003677; F:DNA binding; IDA:MGI.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; ISO:MGI.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:MGI.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central.
DR GO; GO:0003690; F:double-stranded DNA binding; ISO:MGI.
DR GO; GO:0019904; F:protein domain specific binding; ISO:MGI.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:MGI.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISO:MGI.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:MGI.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:MGI.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; ISO:MGI.
DR GO; GO:0061144; P:alveolar secondary septum development; IMP:MGI.
DR GO; GO:0048646; P:anatomical structure formation involved in morphogenesis; IGI:MGI.
DR GO; GO:0009653; P:anatomical structure morphogenesis; IBA:GO_Central.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0006338; P:chromatin remodeling; IDA:UniProtKB.
DR GO; GO:0061448; P:connective tissue development; IGI:MGI.
DR GO; GO:0071542; P:dopaminergic neuron differentiation; IMP:MGI.
DR GO; GO:0021904; P:dorsal/ventral neural tube patterning; IGI:MGI.
DR GO; GO:0060743; P:epithelial cell maturation involved in prostate gland development; IMP:MGI.
DR GO; GO:0060441; P:epithelial tube branching involved in lung morphogenesis; IGI:MGI.
DR GO; GO:0060738; P:epithelial-mesenchymal signaling involved in prostate gland development; IGI:MGI.
DR GO; GO:0042593; P:glucose homeostasis; IMP:MGI.
DR GO; GO:0042445; P:hormone metabolic process; IMP:MGI.
DR GO; GO:0030324; P:lung development; IGI:MGI.
DR GO; GO:0060487; P:lung epithelial cell differentiation; IGI:MGI.
DR GO; GO:0060425; P:lung morphogenesis; IMP:MGI.
DR GO; GO:0010719; P:negative regulation of epithelial to mesenchymal transition; ISO:MGI.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:MGI.
DR GO; GO:0030182; P:neuron differentiation; IMP:MGI.
DR GO; GO:0048665; P:neuron fate specification; IGI:MGI.
DR GO; GO:0007219; P:Notch signaling pathway; IDA:MGI.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISO:MGI.
DR GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; ISO:MGI.
DR GO; GO:1904340; P:positive regulation of dopaminergic neuron differentiation; IMP:MGI.
DR GO; GO:0033148; P:positive regulation of intracellular estrogen receptor signaling pathway; ISO:MGI.
DR GO; GO:0045931; P:positive regulation of mitotic cell cycle; ISO:MGI.
DR GO; GO:0045880; P:positive regulation of smoothened signaling pathway; IGI:MGI.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:MGI.
DR GO; GO:0060740; P:prostate gland epithelium morphogenesis; IMP:MGI.
DR GO; GO:0060741; P:prostate gland stromal morphogenesis; IMP:MGI.
DR GO; GO:0051726; P:regulation of cell cycle; IDA:MGI.
DR GO; GO:0010468; P:regulation of gene expression; IGI:MGI.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IMP:MGI.
DR GO; GO:1902691; P:respiratory basal cell differentiation; IMP:MGI.
DR GO; GO:0032355; P:response to estradiol; ISO:MGI.
DR GO; GO:0060528; P:secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development; IMP:MGI.
DR GO; GO:0007224; P:smoothened signaling pathway; IGI:MGI.
DR GO; GO:0035239; P:tube morphogenesis; IMP:MGI.
DR CDD; cd00059; FH; 1.
DR Gene3D; 1.10.10.10; -; 1.
DR InterPro; IPR013638; Fork-head_N.
DR InterPro; IPR001766; Fork_head_dom.
DR InterPro; IPR018533; Forkhead_box_C.
DR InterPro; IPR018122; TF_fork_head_CS_1.
DR InterPro; IPR030456; TF_fork_head_CS_2.
DR InterPro; IPR036388; WH-like_DNA-bd_sf.
DR InterPro; IPR036390; WH_DNA-bd_sf.
DR Pfam; PF00250; Forkhead; 1.
DR Pfam; PF08430; Forkhead_N; 1.
DR Pfam; PF09354; HNF_C; 1.
DR PRINTS; PR00053; FORKHEAD.
DR SMART; SM00339; FH; 1.
DR SUPFAM; SSF46785; SSF46785; 1.
DR PROSITE; PS00657; FORK_HEAD_1; 1.
DR PROSITE; PS00658; FORK_HEAD_2; 1.
DR PROSITE; PS50039; FORK_HEAD_3; 1.
PE 1: Evidence at protein level;
KW Activator; Chromatin regulator; Developmental protein; DNA-binding;
KW Nucleus; Phosphoprotein; Reference proteome; Repressor; Transcription;
KW Transcription regulation.
FT CHAIN 1..468
FT /note="Hepatocyte nuclear factor 3-alpha"
FT /id="PRO_0000091793"
FT DNA_BIND 169..260
FT /note="Fork-head"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00089"
FT REGION 251..288
FT /note="Essential for DNA binding"
FT REGION 269..396
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 330..358
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 303
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P55317"
FT MOD_RES 327
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P55317"
FT CONFLICT 121
FT /note="A -> V (in Ref. 1; CAA52890)"
FT /evidence="ECO:0000305"
FT CONFLICT 307
FT /note="R -> W (in Ref. 1; CAA52890)"
FT /evidence="ECO:0000305"
FT CONFLICT 389
FT /note="H -> R (in Ref. 2; AAA86760)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 468 AA; 48854 MW; 8513D17623D434FD CRC64;
MLGTVKMEGH ESNDWNSYYA DTQEAYSSVP VSNMNSGLGS MNSMNTYMTM NTMTTSGNMT
PASFNMSYAN TGLGAGLSPG AVAGMPGASA GAMNSMTAAG VTAMGTALSP GGMGSMGAQP
ATSMNGLGPY AAAMNPCMSP MAYAPSNLGR SRAGGGGDAK TFKRSYPHAK PPYSYISLIT
MAIQQAPSKM LTLSEIYQWI MDLFPYYRQN QQRWQNSIRH SLSFNDCFVK VARSPDKPGK
GSYWTLHPDS GNMFENGCYL RRQKRFKCEK QPGAGGGSGG GGSKGGPESR KDPSGPGNPS
AESPLHRGVH GKASQLEGAP APGPAASPQT LDHSGATATG GASELKSPAS SSAPPISSGP
GALASVPPSH PAHGLAPHES QLHLKGDPHY SFNHPFSINN LMSSSEQQHK LDFKAYEQAL
QYSPYGATLP ASLPLGSASV ATRSPIEPSA LEPAYYQGVY SRPVLNTS
