FOXO1_BOVIN
ID FOXO1_BOVIN Reviewed; 624 AA.
AC E1BPQ1;
DT 03-OCT-2012, integrated into UniProtKB/Swiss-Prot.
DT 16-NOV-2011, sequence version 2.
DT 03-AUG-2022, entry version 86.
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 Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Hereford;
RX PubMed=19393038; DOI=10.1186/gb-2009-10-4-r42;
RA Zimin A.V., Delcher A.L., Florea L., Kelley D.R., Schatz M.C., Puiu D.,
RA Hanrahan F., Pertea G., Van Tassell C.P., Sonstegard T.S., Marcais G.,
RA Roberts M., Subramanian P., Yorke J.A., Salzberg S.L.;
RT "A whole-genome assembly of the domestic cow, Bos taurus.";
RL Genome Biol. 10:R42.01-R42.10(2009).
CC -!- FUNCTION: Transcription factor that is the main target of insulin
CC signaling and regulates metabolic homeostasis in response to oxidative
CC stress. Binds to the insulin response element (IRE) with consensus
CC sequence 5'-TT[G/A]TTTTG-3' and the related Daf-16 family binding
CC element (DBE) with consensus sequence 5'-TT[G/A]TTTAC-3'. Activity
CC suppressed by insulin. Main regulator of redox balance and osteoblast
CC numbers and controls bone mass. Orchestrates the endocrine function of
CC the skeleton in regulating glucose metabolism. Also acts as a key
CC regulator of chondrogenic commitment of skeletal progenitor cells in
CC 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.
CC Acts synergistically with ATF4 to suppress osteocalcin/BGLAP activity,
CC increasing glucose levels and triggering glucose intolerance and
CC insulin insensitivity. Also suppresses the transcriptional activity of
CC RUNX2, an upstream activator of osteocalcin/BGLAP. Acts as an inhibitor
CC of glucose sensing in pancreatic beta cells by acting as a
CC transcription repressor and suppressing expression of PDX1. In
CC hepatocytes, promotes gluconeogenesis by acting together with PPARGC1A
CC and CEBPA to activate the expression of genes such as IGFBP1, G6PC1 and
CC PCK1 (By similarity). Also promotes gluconeogenesis by directly
CC promoting expression of PPARGC1A and G6PC1 (By similarity). Important
CC regulator of cell death acting downstream of CDK1, PKB/AKT1 and
CC STK4/MST1 (By similarity). Promotes neural cell death (By similarity).
CC Mediates insulin action on adipose tissue (By similarity). Regulates
CC the 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:A4L7N3,
CC ECO:0000250|UniProtKB:G3V7R4, ECO:0000250|UniProtKB:Q12778,
CC ECO:0000250|UniProtKB:Q9R1E0}.
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 -!- PTM: Phosphorylation by NLK promotes nuclear export and inhibits the
CC transcriptional activity. In response to growth factors,
CC phosphorylation on Thr-24, Ser-226 and Ser-292 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-226 decreases DNA-binding activity and promotes
CC the phosphorylation of Thr-24 and Ser-289, permitting phosphorylation
CC of Ser-292 and Ser-295, 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-299 is independent of IGF1
CC and leads to reduced function. Dephosphorylated on Thr-24 and Ser-226
CC by PP2A in beta-cells under oxidative stress leading to nuclear
CC retention. Phosphorylation of Ser-219 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-182, upon oxidative stress, inhibits binding to 14-3-3 proteins and
CC nuclear export (By similarity). PPIA/CYPA promotes its
CC dephosphorylation on Ser-226 (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-226 and
CC is increased by oxidative stress. {ECO:0000250|UniProtKB:Q9R1E0}.
CC -!- PTM: Acetylated. Acetylation at Lys-232 and Lys-244 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-226. 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-393, promoting its
CC localization to the nucleus and transcription factor activity.
CC Deacetylation at Lys-393 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; DAAA02032974; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; DAAA02032975; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; DAAA02032976; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; DAAA02032977; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; DAAA02032978; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; DAAA02032979; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; DAAA02032980; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR AlphaFoldDB; E1BPQ1; -.
DR SMR; E1BPQ1; -.
DR STRING; 9913.ENSBTAP00000053389; -.
DR PaxDb; E1BPQ1; -.
DR PRIDE; E1BPQ1; -.
DR eggNOG; KOG2294; Eukaryota.
DR HOGENOM; CLU_023456_1_1_1; -.
DR InParanoid; E1BPQ1; -.
DR OrthoDB; 1160384at2759; -.
DR TreeFam; TF315583; -.
DR Proteomes; UP000009136; Unplaced.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
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; IBA:GO_Central.
DR GO; GO:0045599; P:negative regulation of fat cell differentiation; ISS:UniProtKB.
DR GO; GO:0046676; P:negative regulation of insulin secretion; ISS:UniProtKB.
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: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 3: Inferred from homology;
KW Acetylation; Activator; Apoptosis; Autophagy; Cytoplasm; Differentiation;
KW DNA-binding; Methylation; Nucleus; Phosphoprotein; Reference proteome;
KW Transcription; Transcription regulation; Ubl conjugation.
FT CHAIN 1..624
FT /note="Forkhead box protein O1"
FT /id="PRO_0000419243"
FT DNA_BIND 130..224
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 94..128
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 181..188
FT /note="DNA-binding"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT REGION 204..306
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 204..207
FT /note="DNA-binding"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT REGION 253..532
FT /note="Sufficient for interaction with NLK"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT REGION 333..428
FT /note="Required for interaction with RUNX2"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOTIF 221..223
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250"
FT MOTIF 431..435
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 250..300
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 128
FT /note="DNA-binding"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT SITE 135
FT /note="DNA-binding"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT SITE 195
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 182
FT /note="Phosphoserine; by STK4/MST1"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 188
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 204
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 205
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 215
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 218
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 219
FT /note="Phosphoserine; by CDK1"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 221
FT /note="Omega-N-methylarginine; by PRMT1"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 223
FT /note="Omega-N-methylarginine; by PRMT1"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 226
FT /note="Phosphoserine; by PKB/AKT1 and SGK1"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 232
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 235
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 244
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 257
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 268
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 289
FT /note="Phosphoserine; by PKB/AKT1"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 292
FT /note="Phosphoserine; by CK1 and SGK1"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 295
FT /note="Phosphoserine; by CK1"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 299
FT /note="Phosphoserine; by DYRK1A"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
FT MOD_RES 303
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9R1E0"
FT MOD_RES 393
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q12778"
SQ SEQUENCE 624 AA; 66356 MW; B6864B511D282A49 CRC64;
MAEAPQVVEI DPDFEPLPRP RSCTWPLPRP EFSQSNSATS SPAPSGGAAA NPDGAAGLPS
ASAAAVNADF MSNLSLLEES GDFQQAPGSV AAAAPLSQHP PVPPAAAAAA AGGQLAGQPR
KSSSSRRNAW GNLSYADLIT KAIESSAEKR LTLSQIYEWM VKSVPYFKDK GDSNSSAGWK
NSIRHNLSLH SKFIRVQNEG TGKSSWWMLN PEGGKSGKSP RRRAASMDNN SKFAKSRGRA
AKKKASLQSG QEGAGDSPGS QFSKWPASPG SHSNDDFDNW STFRPRTSSN ASTISGRLSP
IMTEQDDLGD GDVHSMVYPP SAAKMASTLP SLSEISNPEN MENLLDNLNL LSSPTSLTVS
TQSSPGTMMQ QTPCYSFAPP NTSLNSPTPN YQKYTYGQSS MSPLPQMPMQ TLQDNKSSYG
GMSQYCAPGL LKELLTSDSP PHNDIMTPVD PGVAQANSRV LGQSVLMGPN SVMPAYGGQA
SHNKMMTPSS HTHPGHAQST SAVNGRALPH AVNTMPHTSG MNRLAPVKTA LQVPLAHPMQ
MSALGGYSSV SSCNGYGRMG VLHQEKLPSD LDGMFIERLD CDMESIIRND LMDGDTLDFN
FDNVLPNQSF PHSVKTTTHS WVSG
