FOXO1_PIG
ID FOXO1_PIG Reviewed; 662 AA.
AC A4L7N3;
DT 03-OCT-2012, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2007, sequence version 1.
DT 03-AUG-2022, entry version 94.
DE RecName: Full=Forkhead box protein O1;
DE AltName: Full=Forkhead box protein O1A;
DE AltName: Full=Forkhead in rhabdomyosarcoma;
GN Name=FOXO1; Synonyms=FOXO1A;
OS Sus scrofa (Pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX NCBI_TaxID=9823;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, AND INDUCTION.
RX PubMed=18293098; DOI=10.1007/s11033-007-9163-6;
RA Pang W.J., Yu T.Y., Bai L., Yang Y.J., Yang G.S.;
RT "Tissue expression of porcine FoxO1 and its negative regulation during
RT primary preadipocyte differentiation.";
RL Mol. Biol. Rep. 36:165-176(2009).
CC -!- FUNCTION: Transcription factor that is the main target of insulin
CC signaling and regulates metabolic homeostasis in response to oxidative
CC stress (PubMed:18293098). Binds to the insulin response element (IRE)
CC with consensus sequence 5'-TT[G/A]TTTTG-3' and the related Daf-16
CC family binding element (DBE) with consensus sequence 5'-TT[G/A]TTTAC-3'
CC (By similarity). Activity suppressed by insulin (By similarity). Main
CC regulator of redox balance and osteoblast numbers and controls bone
CC mass (By similarity). Orchestrates the endocrine function of the
CC skeleton in regulating glucose metabolism (By similarity). Also acts as
CC a key regulator of chondrogenic commitment of skeletal progenitor cells
CC in response to lipid availability: when lipids levels are low,
CC translocates to the nucleus and promotes expression of SOX9, which
CC induces chondrogenic commitment and suppresses fatty acid oxidation (By
CC similarity). Acts synergistically with ATF4 to suppress
CC osteocalcin/BGLAP activity, increasing glucose levels and triggering
CC glucose intolerance and insulin insensitivity (By similarity). Also
CC suppresses the transcriptional activity of RUNX2, an upstream activator
CC of osteocalcin/BGLAP (By similarity). Acts as an inhibitor of glucose
CC sensing in pancreatic beta cells by acting as a transcription repressor
CC and suppressing expression of PDX1 (By similarity). In hepatocytes,
CC promotes gluconeogenesis by acting together with PPARGC1A and CEBPA to
CC activate the expression of genes such as IGFBP1, G6PC1 and PCK1 (By
CC similarity). Also promotes gluconeogenesis by directly promoting
CC expression of PPARGC1A and G6PC1 (By similarity). Important regulator
CC of cell death acting downstream of CDK1, PKB/AKT1 and STK4/MST1 (By
CC similarity). Promotes neural cell death (By similarity). Mediates
CC insulin action on adipose tissue (By similarity). Regulates the
CC expression of adipogenic genes such as PPARG during preadipocyte
CC differentiation and, adipocyte size and adipose tissue-specific gene
CC expression in response to excessive calorie intake (By similarity).
CC Regulates the transcriptional activity of GADD45A and repair of nitric
CC oxide-damaged DNA in beta-cells (By similarity). Required for the
CC autophagic cell death induction in response to starvation or oxidative
CC stress in a transcription-independent manner (By similarity). Mediates
CC the function of MLIP in cardiomyocytes hypertrophy and cardiac
CC remodeling (By similarity). Regulates endothelial cell (EC) viability
CC and apoptosis in a PPIA/CYPA-dependent manner via transcription of CCL2
CC and BCL2L11 which are involved in EC chemotaxis and apoptosis (By
CC similarity). {ECO:0000250|UniProtKB:Q12778,
CC ECO:0000250|UniProtKB:Q9R1E0, ECO:0000269|PubMed:18293098}.
CC -!- SUBUNIT: Interacts with LRPPRC. Interacts with RUNX2; the interaction
CC inhibits RUNX2 transcriptional activity and mediates the IGF1/insulin-
CC dependent BGLAP expression in osteoblasts Interacts with PPP2R1A; the
CC interaction regulates the dephosphorylation of FOXO1 at Thr-24 and Ser-
CC 263 leading to its nuclear import. Interacts with NLK. Interacts with
CC SIRT1; the interaction results in the deacetylation of FOXO1 leading to
CC activation of FOXO1-mediated transcription of genes involved in DNA
CC repair and stress resistance. Binds to CDK1. Interacts with the 14-3-3
CC proteins, YWHAG and YWHAZ; the interactions require insulin-stimulated
CC phosphorylation on Thr-24, promote nuclear exit and loss of
CC transcriptional activity. Interacts with SKP2; the interaction
CC ubiquitinates FOXO1 leading to its proteosomal degradation. The
CC interaction requires the presence of KRIT1. Interacts (via the C-
CC terminal half) with ATF4 (via its DNA binding domain); the interaction
CC occurs in osteoblasts, regulates glucose homeostasis via suppression of
CC beta-cell proliferation and subsequent decrease in insulin production.
CC Interacts with PRMT1; the interaction methylates FOXO1, prevents
CC PKB/AKT1 phosphorylation and retains FOXO1 in the nucleus. Interacts
CC with EP300 and CREBBP; the interactions acetylate FOXO1. Interacts with
CC SIRT2; the interaction is disrupted in response to oxidative stress or
CC serum deprivation, leading to increased level of acetylated FOXO1,
CC which promotes stress-induced autophagy by stimulating E1-like
CC activating enzyme ATG7. Interacts (acetylated form) with ATG7; the
CC interaction is increased in response to oxidative stress or serum
CC deprivation and promotes the autophagic process leading to cell death.
CC Interacts (acetylated form) with PPARG. Interacts with XBP1; this
CC interaction is direct and leads to FOXO1 ubiquitination and degradation
CC via the proteasome pathway (By similarity). Interacts (via the Fork-
CC head domain) with CEBPA; the interaction increases when FOXO1 is
CC deacetylated. Interacts with WDFY2. Forms a complex with WDFY2 and AKT1
CC (By similarity). Interacts with CRY1 (By similarity). Interacts with
CC PPIA/CYPA; the interaction promotes FOXO1 dephosphorylation, nuclear
CC accumulation and transcriptional activity (By similarity). Interacts
CC with TOX4; FOXO1 is required for full induction of TOX4-dependent
CC activity and the interaction is inhibited by insulin (By similarity).
CC {ECO:0000250|UniProtKB:Q12778, ECO:0000250|UniProtKB:Q9R1E0}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9R1E0}. Nucleus
CC {ECO:0000250|UniProtKB:Q9R1E0}. Note=Shuttles between the cytoplasm and
CC nucleus (By similarity). Largely nuclear in unstimulated cells (By
CC similarity). In osteoblasts, colocalizes with ATF4 and RUNX2 in the
CC nucleus. Serum deprivation increases localization to the nucleus,
CC leading to activate expression of SOX9 and subsequent chondrogenesis
CC (By similarity). Insulin-induced phosphorylation at Ser-253 by PKB/AKT1
CC leads, via stimulation of Thr-24 phosphorylation, to binding of 14-3-3
CC proteins and nuclear export to the cytoplasm where it is degraded by
CC the ubiquitin-proteosomal pathway (By similarity). Phosphorylation at
CC Ser-249 by CDK1 disrupts binding of 14-3-3 proteins and promotes
CC nuclear accumulation (By similarity). Phosphorylation by NLK results in
CC nuclear export (By similarity). Translocates to the nucleus upon
CC oxidative stress-induced phosphorylation at Ser-212 by STK4/MST1 (By
CC similarity). SGK1-mediated phosphorylation also results in nuclear
CC translocation. Retained in the nucleus under stress stimuli including
CC oxidative stress, nutrient deprivation or nitric oxide. Methylated form
CC is nuclear (By similarity). PPIA/CYPA stimulates its nuclear
CC accumulation (By similarity). Deacetylation by SIRT6, promotes its
CC translocation into the cytoplasm (By similarity).
CC {ECO:0000250|UniProtKB:Q12778, ECO:0000250|UniProtKB:Q9R1E0}.
CC -!- TISSUE SPECIFICITY: Highly in subcutaneous adipose and visceral adipose
CC tissues. Levels higher in piglets than in adults. Also expressed at
CC lower levels in liver and muscle. {ECO:0000269|PubMed:18293098}.
CC -!- INDUCTION: Up-regulated during preadipocyte differentiation. Down-
CC regulated in these cells on treatment with IGF1.
CC {ECO:0000269|PubMed:18293098}.
CC -!- PTM: Phosphorylation by NLK promotes nuclear export and inhibits the
CC transcriptional activity. In response to growth factors,
CC phosphorylation on Thr-24, Ser-263 and Ser-326 by PKB/AKT1 promotes
CC nuclear export and inactivation of transactivational activity.
CC Phosphorylation on Thr-24 is required for binding 14-3-3 proteins.
CC Phosphorylation of Ser-263 decreases DNA-binding activity and promotes
CC the phosphorylation of Thr-24 and Ser-326, permitting phosphorylation
CC of Ser-329 and Ser-332, probably by CDK1, leading to nuclear exclusion
CC and loss of function. Stress signals, such as response to oxygen or
CC nitric oxide, attenuate the PKB/AKT1-mediated phosphorylation leading
CC to nuclear retention. Phosphorylation of Ser-336 is independent of IGF1
CC and leads to reduced function. Dephosphorylated on Thr-24 and Ser-263
CC by PP2A in beta-cells under oxidative stress leading to nuclear
CC retention. Phosphorylation of Ser-256 by CDK1 disrupts binding of 14-3-
CC 3 proteins leading to nuclear accumulation and has no effect on DNA
CC binding nor transcriptional activity. Phosphorylation by STK4/MST1 on
CC Ser-219, upon oxidative stress, inhibits binding to 14-3-3 proteins and
CC nuclear export (By similarity). PPIA/CYPA promotes its
CC dephosphorylation on Ser-263 (By similarity).
CC {ECO:0000250|UniProtKB:Q12778, ECO:0000250|UniProtKB:Q9R1E0}.
CC -!- PTM: Ubiquitinated by SKP2. Ubiquitination leads to proteasomal
CC degradation (By similarity). {ECO:0000250|UniProtKB:Q12778}.
CC -!- PTM: Methylation inhibits AKT1-mediated phosphorylation at Ser-263 and
CC is increased by oxidative stress. {ECO:0000250|UniProtKB:Q9R1E0}.
CC -!- PTM: Acetylated. Acetylation at Lys-269 and Lys-281 are necessary for
CC autophagic cell death induction. Deacetylated by SIRT2 in response to
CC oxidative stress or serum deprivation, thereby negatively regulating
CC FOXO1-mediated autophagic cell death. Once in the nucleus, acetylated
CC by CREBBP/EP300. Acetylation diminishes the interaction with target DNA
CC and attenuates the transcriptional activity. It increases the
CC phosphorylation at Ser-263. Deacetylation by SIRT1 results in
CC reactivation of the transcriptional activity. Oxidative stress by
CC hydrogen peroxide treatment appears to promote deacetylation and
CC uncoupling of insulin-induced phosphorylation. By contrast, resveratrol
CC acts independently of acetylation. Acetylated at Lys-430, promoting its
CC localization to the nucleus and transcription factor activity.
CC Deacetylation at Lys-430 by SIRT6, promotes its translocation into the
CC cytoplasm, preventing its transcription factor activity. Deacetylation
CC and subsequent inhibition by SIRT6 has different effects depending on
CC cell types: it inhibits gluconeogenesis in hepatocytes, promotes
CC glucose sensing in pancreatic beta-cells and regulates lipid catabolism
CC in brown adipocytes. {ECO:0000250|UniProtKB:Q12778}.
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DR EMBL; EF453379; ABO47824.1; -; mRNA.
DR RefSeq; NP_999179.2; NM_214014.2.
DR AlphaFoldDB; A4L7N3; -.
DR SMR; A4L7N3; -.
DR STRING; 9823.ENSSSCP00000010000; -.
DR PaxDb; A4L7N3; -.
DR PRIDE; A4L7N3; -.
DR GeneID; 397077; -.
DR CTD; 2308; -.
DR eggNOG; KOG2294; Eukaryota.
DR InParanoid; A4L7N3; -.
DR Proteomes; UP000008227; Unplaced.
DR Proteomes; UP000314985; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IDA:AgBase.
DR GO; GO:0005634; C:nucleus; IDA:AgBase.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; ISS:UniProtKB.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; ISS:UniProtKB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central.
DR GO; GO:0051721; F:protein phosphatase 2A binding; ISS:UniProtKB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISS:UniProtKB.
DR GO; GO:0043565; F:sequence-specific DNA binding; ISS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; ISS:UniProtKB.
DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; ISS:UniProtKB.
DR GO; GO:0071455; P:cellular response to hyperoxia; ISS:UniProtKB.
DR GO; GO:0032869; P:cellular response to insulin stimulus; ISS:UniProtKB.
DR GO; GO:0071732; P:cellular response to nitric oxide; ISS:UniProtKB.
DR GO; GO:0034599; P:cellular response to oxidative stress; ISS:UniProtKB.
DR GO; GO:0009267; P:cellular response to starvation; ISS:UniProtKB.
DR GO; GO:0008286; P:insulin receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0045599; P:negative regulation of fat cell differentiation; IDA:UniProtKB.
DR GO; GO:0010629; P:negative regulation of gene expression; IMP:AgBase.
DR GO; GO:0046676; P:negative regulation of insulin secretion; ISS:UniProtKB.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:AgBase.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; IDA:AgBase.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0010508; P:positive regulation of autophagy; ISS:UniProtKB.
DR GO; GO:1903661; P:positive regulation of complement-dependent cytotoxicity; IMP:AgBase.
DR GO; GO:0045722; P:positive regulation of gluconeogenesis; ISS:UniProtKB.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; ISS:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0070542; P:response to fatty acid; ISS:UniProtKB.
DR CDD; cd00059; FH; 1.
DR Gene3D; 1.10.10.10; -; 1.
DR InterPro; IPR001766; Fork_head_dom.
DR InterPro; IPR032067; FOXO-TAD.
DR InterPro; IPR032068; FOXO_KIX-bd.
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; PF16676; FOXO-TAD; 1.
DR Pfam; PF16675; FOXO_KIX_bdg; 1.
DR PRINTS; PR00053; FORKHEAD.
DR SMART; SM00339; FH; 1.
DR SUPFAM; SSF46785; SSF46785; 1.
DR PROSITE; PS00658; FORK_HEAD_2; 1.
DR PROSITE; PS50039; FORK_HEAD_3; 1.
PE 2: Evidence at transcript level;
KW Acetylation; Activator; Apoptosis; Autophagy; Cytoplasm; Differentiation;
KW DNA-binding; Methylation; Nucleus; Phosphoprotein; Reference proteome;
KW Transcription; Transcription regulation; Ubl conjugation.
FT CHAIN 1..662
FT /note="Forkhead box protein O1"
FT /id="PRO_0000419244"
FT DNA_BIND 167..261
FT /note="Fork-head"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00089"
FT REGION 1..62
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 122..165
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 218..225
FT /note="DNA-binding"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT REGION 241..342
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 241..244
FT /note="DNA-binding"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT REGION 290..570
FT /note="Sufficient for interaction with NLK"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT REGION 370..466
FT /note="Required for interaction with RUNX2"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOTIF 258..260
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250"
FT MOTIF 469..473
FT /note="Required for interaction with SIRT1"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT COMPBIAS 28..46
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 125..144
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 287..337
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 165
FT /note="DNA-binding"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT SITE 172
FT /note="DNA-binding"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT SITE 232
FT /note="DNA-binding"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 24
FT /note="Phosphothreonine; by PKB/AKT1 or PKB/AKT2 and SGK1"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 219
FT /note="Phosphoserine; by STK4/MST1"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 225
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 241
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 242
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 252
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 255
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 256
FT /note="Phosphoserine; by CDK1"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 258
FT /note="Omega-N-methylarginine; by PRMT1"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 260
FT /note="Omega-N-methylarginine; by PRMT1"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 263
FT /note="Phosphoserine; by PKB/AKT1 and SGK1"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 269
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 272
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 281
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 294
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 305
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 326
FT /note="Phosphoserine; by PKB/AKT1"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 329
FT /note="Phosphoserine; by CK1 and SGK1"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 332
FT /note="Phosphoserine; by CK1"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 336
FT /note="Phosphoserine; by DYRK1A"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 340
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 430
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
SQ SEQUENCE 662 AA; 69921 MW; 0FA0E7E0C9B651C8 CRC64;
MAEAPQVVEI DPDFEPLPRP RSCTWPLPRP EFSQSNSATS SPAPSGGAAA NPDAAAGLPS
ASAAAVNADF MSNLSLLEES EDFPQAPGSV AAAAAAAAAV AAAAAAAATG GLCGDFQGPE
AGCLHPAPPQ QPPPPGPLSQ HPPVPPAAAG SLAGQPRKSS SSRRNAWGNL SYADLITKAI
ESSAEKRLTL SQIYEWMVKS VPYFKDKGDS NSSAGWKNSI RHNLSLHSKF IRVQNEGTGK
SSWWMLNPEG GKSGKSPRRR AASMDNNSKF AKSRGRAAKK KASLQSGQEG AGDSPGSQFS
KWPASPGSHS NDDFDNWSTF RPRTSSNAST ISGRLSPIMT EQDDLGNGDV HSMVYPPSAA
KMASTLPSLS EISNPENMEN LLDNLNLLSS PTSLTVSTQS SPGTIMQQTP CYSFAPPNTS
LNSPSPNYQK YTYGQSSMSP LPQMPMQTLQ DSKSSYGGMA QYNCAAGLLK ELLTSDSPPH
NDIMTPVDPG VAQPNSRVLG QNVLMGPSSV MPAYGGQASH NKMMNPSSHS HPGHAQSTSA
VNGRALPHAV NTMPHASGMN RLTQEKTALQ VPLPHPMQMN ALGGYSPAST CNGYGRMGLL
HQEKLPSDLD GMFIERLDCD MESIIRNDLM DGDTLDFNFD NVLPNQSFPH SVKTTTHSWV
SG
