HIF3A_HUMAN
ID HIF3A_HUMAN Reviewed; 669 AA.
AC Q9Y2N7; B0M185; B4DNA2; I6L988; Q58A43; Q66K72; Q8WXA1; Q96K34; Q9H7Z9;
AC Q9HAI2;
DT 17-APR-2007, integrated into UniProtKB/Swiss-Prot.
DT 17-APR-2007, sequence version 2.
DT 03-AUG-2022, entry version 170.
DE RecName: Full=Hypoxia-inducible factor 3-alpha {ECO:0000303|PubMed:11573933};
DE Short=HIF-3-alpha {ECO:0000303|PubMed:11573933};
DE Short=HIF3-alpha;
DE AltName: Full=Basic-helix-loop-helix-PAS protein MOP7;
DE AltName: Full=Class E basic helix-loop-helix protein 17;
DE Short=bHLHe17;
DE AltName: Full=HIF3-alpha-1;
DE AltName: Full=Inhibitory PAS domain protein;
DE Short=IPAS;
DE AltName: Full=Member of PAS protein 7;
DE AltName: Full=PAS domain-containing protein 7;
GN Name=HIF3A {ECO:0000312|HGNC:HGNC:15825}; Synonyms=BHLHE17, MOP7, PASD7;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION (ISOFORM 2), AND TISSUE
RP SPECIFICITY.
RC TISSUE=Kidney;
RX PubMed=11573933; DOI=10.1006/bbrc.2001.5659;
RA Hara S., Hamada J., Kobayashi C., Kondo Y., Imura N.;
RT "Expression and characterization of hypoxia-inducible factor (HIF)-3alpha
RT in human kidney: suppression of HIF-mediated gene expression by HIF-
RT 3alpha.";
RL Biochem. Biophys. Res. Commun. 287:808-813(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RA Cheng J.Q.;
RT "Cloning and characterization of human inhibitory PAS domain protein.";
RL Submitted (DEC-2001) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4), FUNCTION (ISOFORM 4), INTERACTION
RP WITH HIF1A AND ARNT (ISOFORM 4), INDUCTION (ISOFORM 4), AND TISSUE
RP SPECIFICITY.
RC TISSUE=Cerebellum;
RX PubMed=16126907; DOI=10.1096/fj.05-3788com;
RA Maynard M.A., Evans A.J., Hosomi T., Hara S., Jewett M.A., Ohh M.;
RT "Human HIF-3alpha4 is a dominant-negative regulator of HIF-1 and is down-
RT regulated in renal cell carcinoma.";
RL FASEB J. 19:1396-1406(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RC TISSUE=Kidney;
RA Hara S., Hosomi T., Mita M., Sakaue M., Kondo Y.;
RT "HIF-3alpha2, one of splicing variants of human hypoxia-inducible factor-
RT 3alpha, functions as an inhibitor of hypoxia-induced gene expression and
RT tumor growth.";
RL Submitted (FEB-2007) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 7), NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 1-626 (ISOFORM 5), NUCLEOTIDE SEQUENCE
RP [LARGE SCALE MRNA] OF 1-233 (ISOFORM 6), AND VARIANT ARG-343.
RC TISSUE=Embryo, Heart, and Ovary;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 4), AND VARIANT
RP ARG-343.
RC TISSUE=Brain, and Pancreas;
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 [9]
RP INTERACTION WITH VHL (ISOFORM 2), ALTERNATIVE SPLICING, UBIQUITINATION AT
RP LYS-467 AND LYS-570, HYDROXYLATION AT PRO-492, TISSUE SPECIFICITY, AND
RP MUTAGENESIS OF LYS-467; PRO-492 AND LYS-570.
RX PubMed=12538644; DOI=10.1074/jbc.m208681200;
RA Maynard M.A., Qi H., Chung J., Lee E.H., Kondo Y., Hara S., Conaway R.C.,
RA Conaway J.W., Ohh M.;
RT "Multiple splice variants of the human HIF-3 alpha locus are targets of the
RT von Hippel-Lindau E3 ubiquitin ligase complex.";
RL J. Biol. Chem. 278:11032-11040(2003).
RN [10]
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INDUCTION.
RX PubMed=16775626; DOI=10.1038/sj.cr.7310072;
RA Li Q.F., Wang X.R., Yang Y.W., Lin H.;
RT "Hypoxia upregulates hypoxia inducible factor (HIF)-3alpha expression in
RT lung epithelial cells: characterization and comparison with HIF-1alpha.";
RL Cell Res. 16:548-558(2006).
RN [11]
RP FUNCTION (ISOFORM 4), AND INTERACTION WITH EPAS1 (ISOFORM 4).
RX PubMed=17998805; DOI=10.4161/cc.6.22.4947;
RA Maynard M.A., Evans A.J., Shi W., Kim W.Y., Liu F.F., Ohh M.;
RT "Dominant-negative HIF-3 alpha 4 suppresses VHL-null renal cell carcinoma
RT progression.";
RL Cell Cycle 6:2810-2816(2007).
RN [12]
RP FUNCTION (ISOFORMS 3 AND 4), SUBCELLULAR LOCATION, INDUCTION, AND TISSUE
RP SPECIFICITY.
RX PubMed=19694616; DOI=10.1042/bj20090120;
RA Tanaka T., Wiesener M., Bernhardt W., Eckardt K.U., Warnecke C.;
RT "The human HIF (hypoxia-inducible factor)-3alpha gene is a HIF-1 target
RT gene and may modulate hypoxic gene induction.";
RL Biochem. J. 424:143-151(2009).
RN [13]
RP FUNCTION (ISOFORMS 3 AND 4), ALTERNATIVE SPLICING, TISSUE SPECIFICITY
RP (ISOFORMS 2; 3 AND 4), AND INDUCTION.
RX PubMed=20416395; DOI=10.1016/j.biocel.2010.04.008;
RA Pasanen A., Heikkila M., Rautavuoma K., Hirsila M., Kivirikko K.I.,
RA Myllyharju J.;
RT "Hypoxia-inducible factor (HIF)-3alpha is subject to extensive alternative
RT splicing in human tissues and cancer cells and is regulated by HIF-1 but
RT not HIF-2.";
RL Int. J. Biochem. Cell Biol. 42:1189-1200(2010).
RN [14]
RP FUNCTION (ISOFORMS 3 AND 5), TISSUE SPECIFICITY, AND INDUCTION (ISOFORMS 2;
RP 3 AND 5).
RX PubMed=21069422; DOI=10.1007/s00018-010-0575-4;
RA Augstein A., Poitz D.M., Braun-Dullaeus R.C., Strasser R.H., Schmeisser A.;
RT "Cell-specific and hypoxia-dependent regulation of human HIF-3alpha:
RT inhibition of the expression of HIF target genes in vascular cells.";
RL Cell. Mol. Life Sci. 68:2627-2642(2011).
CC -!- FUNCTION: Acts as a transcriptional regulator in adaptive response to
CC low oxygen tension. Acts as a regulator of hypoxia-inducible gene
CC expression (PubMed:11573933, PubMed:16126907, PubMed:19694616,
CC PubMed:20416395, PubMed:21069422). Functions as an inhibitor of
CC angiogenesis in hypoxic cells of the cornea. Plays a role in the
CC development of the cardiorespiratory system. May also be involved in
CC apoptosis (By similarity). {ECO:0000250|UniProtKB:Q0VBL6,
CC ECO:0000269|PubMed:11573933, ECO:0000269|PubMed:16126907,
CC ECO:0000269|PubMed:19694616, ECO:0000269|PubMed:20416395,
CC ECO:0000269|PubMed:21069422}.
CC -!- FUNCTION: [Isoform 2]: Attenuates the ability of transcription factor
CC HIF1A to bind to hypoxia-responsive elements (HRE) located within the
CC enhancer/promoter of hypoxia-inducible target genes and hence inhibits
CC HRE-driven transcriptional activation. Also inhibits hypoxia-inducible
CC ARNT-mediated gene expression. {ECO:0000269|PubMed:11573933}.
CC -!- FUNCTION: [Isoform 3]: Attenuates the ability of transcription factor
CC HIF1A to bind to hypoxia-responsive elements (HRE) located within the
CC enhancer/promoter of hypoxia-inducible target genes and hence inhibits
CC HRE-driven transcriptional activation. {ECO:0000269|PubMed:19694616,
CC ECO:0000269|PubMed:20416395, ECO:0000269|PubMed:21069422}.
CC -!- FUNCTION: [Isoform 4]: Attenuates the ability of transcription factor
CC HIF1A and EPAS1/HIF2A to bind to hypoxia-responsive elements (HRE)
CC located within the enhancer/promoter of hypoxia-inducible target genes
CC and hence inhibits HRE-driven transcriptional activation
CC (PubMed:16126907, PubMed:17998805, PubMed:19694616, PubMed:20416395).
CC May act as a tumor suppressor and inhibits malignant cell
CC transformation (PubMed:17998805). {ECO:0000269|PubMed:16126907,
CC ECO:0000269|PubMed:17998805, ECO:0000269|PubMed:19694616,
CC ECO:0000269|PubMed:20416395}.
CC -!- FUNCTION: [Isoform 5]: Attenuates the ability of transcription factor
CC HIF1A to bind to hypoxia-responsive elements (HRE) located within the
CC enhancer/promoter of hypoxia-inducible target genes and hence inhibits
CC HRE-driven transcriptional activation. {ECO:0000269|PubMed:21069422}.
CC -!- SUBUNIT: Isoform 2 interacts (via ODD domain) with VHL (via beta
CC domain) (PubMed:12538644). Isoform 4 interacts with HIF1A; the
CC interaction inhibits the binding of HIF1A to hypoxia-responsive element
CC (HRE) and HIF1A/ARNT-dependent transcriptional activation
CC (PubMed:16126907). Isoform 4 interacts with ARNT; the interaction
CC occurs in a HIF1A- and DNA-binding-independent manner and does not
CC induce HIF1A/ARNT-dependent transcriptional activation
CC (PubMed:16126907). Isoform 4 interacts with EPAS1 (PubMed:17998805).
CC Interacts with BAD, BCL2L2 and MCL1 (By similarity).
CC {ECO:0000250|UniProtKB:Q0VBL6, ECO:0000269|PubMed:12538644,
CC ECO:0000269|PubMed:16126907, ECO:0000269|PubMed:17998805}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16775626,
CC ECO:0000269|PubMed:19694616}. Cytoplasm {ECO:0000269|PubMed:19694616}.
CC Nucleus speckle {ECO:0000250|UniProtKB:Q0VBL6}. Mitochondrion
CC {ECO:0000250|UniProtKB:Q0VBL6}. Note=In the nuclei of all periportal
CC and perivenous hepatocytes. In the distal perivenous zone, detected in
CC the cytoplasm of the hepatocytes. Shuttles between the nucleus and the
CC cytoplasm in a CRM1-dependent manner. Colocalizes with BAD in the
CC cytoplasm. Colocalizes with EPAS1 and HIF1A in the nucleus and speckles
CC (By similarity). Localized in the cytoplasm and nuclei under normoxia,
CC but increased in the nucleus under hypoxic conditions
CC (PubMed:19694616). Colocalized with HIF1A in kidney tumors
CC (PubMed:19694616). {ECO:0000250|UniProtKB:Q0VBL6,
CC ECO:0000250|UniProtKB:Q9JHS2, ECO:0000269|PubMed:19694616}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=7;
CC Comment=Additional isoforms seem to exist.
CC {ECO:0000303|PubMed:12538644, ECO:0000303|PubMed:20416395};
CC Name=1;
CC IsoId=Q9Y2N7-1; Sequence=Displayed;
CC Name=2; Synonyms=HIF-3alpha1 {ECO:0000303|PubMed:12538644};
CC IsoId=Q9Y2N7-2; Sequence=VSP_024520;
CC Name=3; Synonyms=HIF-3alpha2 {ECO:0000303|PubMed:12538644};
CC IsoId=Q9Y2N7-3; Sequence=VSP_024526;
CC Name=4; Synonyms=HIF-3alpha4 {ECO:0000303|PubMed:12538644};
CC IsoId=Q9Y2N7-4; Sequence=VSP_024523, VSP_024525;
CC Name=5; Synonyms=HIF-3alpha3 {ECO:0000303|PubMed:12538644};
CC IsoId=Q9Y2N7-5; Sequence=VSP_024519;
CC Name=6; Synonyms=HIF-3alpha6 {ECO:0000303|PubMed:12538644};
CC IsoId=Q9Y2N7-6; Sequence=VSP_024518, VSP_024521;
CC Name=7;
CC IsoId=Q9Y2N7-7; Sequence=VSP_043429;
CC -!- TISSUE SPECIFICITY: Expressed in vascular cells (at protein level)
CC (PubMed:21069422). Expressed in kidney (PubMed:11573933,
CC PubMed:19694616). Expressed in lung epithelial cells (PubMed:16775626).
CC Expressed in endothelial cells (venous and arterial cells from
CC umbilical cord and aortic endothelial cells) and in vascular smooth
CC muscle cells (aorta) (PubMed:21069422). Strongly expressed in the
CC heart, placenta, and skeletal muscle, whereas a weak expression profile
CC was found in the lung, liver, and kidney (PubMed:12538644). Expressed
CC weakly in cell renal cell carcinoma (CC-RCC) compared to normal renal
CC cells (PubMed:16126907). Expression is down-regulated in numerous
CC kidney tumor cells compared to non tumor kidney tissues
CC (PubMed:16126907). Isoform 2 is expressed in heart, placenta, lung,
CC liver, skeletal muscle and pancreas and in numerous cancer cell lines
CC (PubMed:20416395). Isoform 3 and isoform 4 are weakly expressed in
CC heart, placenta, lung, liver, skeletal muscle and pancreas
CC (PubMed:20416395). Isoform 4 is expressed in fetal tissues, such as
CC heart, brain, thymus, lung, liver, skeletal kidney and spleen
CC (PubMed:20416395). Isoform 3 is weakly expressed in fetal tissues, such
CC as liver and kidney (PubMed:20416395). {ECO:0000269|PubMed:11573933,
CC ECO:0000269|PubMed:12538644, ECO:0000269|PubMed:16126907,
CC ECO:0000269|PubMed:16775626, ECO:0000269|PubMed:19694616,
CC ECO:0000269|PubMed:20416395, ECO:0000269|PubMed:21069422}.
CC -!- INDUCTION: Up-regulated by hypoxia (at protein level)
CC (PubMed:16775626). Induced by hypoxia (PubMed:16775626). Isoform 2,
CC isoform 3, isoform 4 and isoform 5 are up-regulated by hypoxia in a
CC HIF1A- and EPAS1/HIF2A-dependent manner (PubMed:19694616,
CC PubMed:20416395, PubMed:21069422). Isoform 4 is down-regulated by
CC hypoxia and up-regulated upon restoring normoxia in embryonic kidney
CC cells (PubMed:16126907). {ECO:0000269|PubMed:16126907,
CC ECO:0000269|PubMed:16775626, ECO:0000269|PubMed:19694616,
CC ECO:0000269|PubMed:20416395, ECO:0000269|PubMed:21069422}.
CC -!- PTM: In normoxia, hydroxylated on Pro-492 in the oxygen-dependent
CC degradation domain (ODD) by prolyl hydroxylase(s) (PHD). The
CC hydroxylated proline promotes interaction with VHL, initiating rapid
CC ubiquitination and subsequent proteasomal degradation.
CC {ECO:0000269|PubMed:12538644}.
CC -!- PTM: Ubiquitinated; ubiquitination occurs in a VHL- and oxygen-
CC dependent pathway and subsequently targeted for proteasomal
CC degradation. {ECO:0000269|PubMed:12538644}.
CC -!- MISCELLANEOUS: [Isoform 5]: Incomplete sequence. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 6]: Incomplete sequence. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAL69947.1; Type=Miscellaneous discrepancy; Note=Intron retention.; Evidence={ECO:0000305};
CC Sequence=BAB13865.1; Type=Miscellaneous discrepancy; Note=Aberrant splicing site.; Evidence={ECO:0000305};
CC Sequence=BAB14824.1; Type=Miscellaneous discrepancy; Note=Unlikely isoform. Aberrant splice sites.; Evidence={ECO:0000305};
CC Sequence=BAB55324.1; Type=Miscellaneous discrepancy; Note=Intron retention.; Evidence={ECO:0000305};
CC Sequence=BAD93355.1; Type=Miscellaneous discrepancy; Note=Intron retention.; Evidence={ECO:0000305};
CC Sequence=BAG07185.1; Type=Miscellaneous discrepancy; Note=Intron retention.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Hypoxia inducible factor entry;
CC URL="https://en.wikipedia.org/wiki/Hypoxia_inducible_factor";
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DR EMBL; AB054067; BAB69689.1; -; mRNA.
DR EMBL; AF463492; AAL69947.1; ALT_SEQ; mRNA.
DR EMBL; AB118749; BAD93355.1; ALT_SEQ; mRNA.
DR EMBL; AB295039; BAG07185.1; ALT_SEQ; mRNA.
DR EMBL; AK021653; BAB13865.1; ALT_SEQ; mRNA.
DR EMBL; AK024095; BAB14824.1; ALT_SEQ; mRNA.
DR EMBL; AK027725; BAB55324.1; ALT_SEQ; mRNA.
DR EMBL; AK297828; BAG60164.1; -; mRNA.
DR EMBL; AC007193; AAD22668.1; -; Genomic_DNA.
DR EMBL; CH471126; EAW57410.1; -; Genomic_DNA.
DR EMBL; BC026308; AAH26308.1; -; mRNA.
DR EMBL; BC080551; AAH80551.1; -; mRNA.
DR CCDS; CCDS12681.2; -. [Q9Y2N7-1]
DR CCDS; CCDS12682.1; -. [Q9Y2N7-2]
DR CCDS; CCDS42580.2; -. [Q9Y2N7-7]
DR PIR; JC7771; JC7771.
DR RefSeq; NP_071907.4; NM_022462.4. [Q9Y2N7-7]
DR RefSeq; NP_690007.1; NM_152794.3. [Q9Y2N7-2]
DR RefSeq; NP_690008.2; NM_152795.3. [Q9Y2N7-1]
DR PDB; 4WN5; X-ray; 1.15 A; A/B=237-347.
DR PDBsum; 4WN5; -.
DR AlphaFoldDB; Q9Y2N7; -.
DR SMR; Q9Y2N7; -.
DR BioGRID; 122143; 5.
DR ELM; Q9Y2N7; -.
DR STRING; 9606.ENSP00000366898; -.
DR iPTMnet; Q9Y2N7; -.
DR PhosphoSitePlus; Q9Y2N7; -.
DR BioMuta; HIF3A; -.
DR DMDM; 145558932; -.
DR MassIVE; Q9Y2N7; -.
DR PaxDb; Q9Y2N7; -.
DR PeptideAtlas; Q9Y2N7; -.
DR PRIDE; Q9Y2N7; -.
DR ProteomicsDB; 85845; -. [Q9Y2N7-1]
DR ProteomicsDB; 85846; -. [Q9Y2N7-2]
DR ProteomicsDB; 85847; -. [Q9Y2N7-3]
DR ProteomicsDB; 85848; -. [Q9Y2N7-4]
DR ProteomicsDB; 85849; -. [Q9Y2N7-5]
DR ProteomicsDB; 85851; -. [Q9Y2N7-7]
DR Antibodypedia; 18071; 386 antibodies from 31 providers.
DR DNASU; 64344; -.
DR Ensembl; ENST00000244303.10; ENSP00000244303.6; ENSG00000124440.16. [Q9Y2N7-7]
DR Ensembl; ENST00000300862.7; ENSP00000300862.3; ENSG00000124440.16. [Q9Y2N7-2]
DR Ensembl; ENST00000377670.9; ENSP00000366898.3; ENSG00000124440.16. [Q9Y2N7-1]
DR GeneID; 64344; -.
DR KEGG; hsa:64344; -.
DR MANE-Select; ENST00000377670.9; ENSP00000366898.3; NM_152795.4; NP_690008.2.
DR UCSC; uc002peh.3; human. [Q9Y2N7-1]
DR CTD; 64344; -.
DR DisGeNET; 64344; -.
DR GeneCards; HIF3A; -.
DR HGNC; HGNC:15825; HIF3A.
DR HPA; ENSG00000124440; Low tissue specificity.
DR MIM; 609976; gene.
DR neXtProt; NX_Q9Y2N7; -.
DR OpenTargets; ENSG00000124440; -.
DR PharmGKB; PA29285; -.
DR VEuPathDB; HostDB:ENSG00000124440; -.
DR eggNOG; KOG3558; Eukaryota.
DR GeneTree; ENSGT00940000161745; -.
DR HOGENOM; CLU_010044_5_0_1; -.
DR InParanoid; Q9Y2N7; -.
DR OMA; AEPRSHF; -.
DR OrthoDB; 547545at2759; -.
DR PhylomeDB; Q9Y2N7; -.
DR TreeFam; TF317772; -.
DR PathwayCommons; Q9Y2N7; -.
DR Reactome; R-HSA-1234158; Regulation of gene expression by Hypoxia-inducible Factor. [Q9Y2N7-1]
DR Reactome; R-HSA-1234176; Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.
DR Reactome; R-HSA-452723; Transcriptional regulation of pluripotent stem cells.
DR Reactome; R-HSA-8951664; Neddylation.
DR SignaLink; Q9Y2N7; -.
DR SIGNOR; Q9Y2N7; -.
DR BioGRID-ORCS; 64344; 16 hits in 1076 CRISPR screens.
DR ChiTaRS; HIF3A; human.
DR GenomeRNAi; 64344; -.
DR Pharos; Q9Y2N7; Tbio.
DR PRO; PR:Q9Y2N7; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q9Y2N7; protein.
DR Bgee; ENSG00000124440; Expressed in mucosa of stomach and 149 other tissues.
DR ExpressionAtlas; Q9Y2N7; baseline and differential.
DR Genevisible; Q9Y2N7; HS.
DR GO; GO:0000785; C:chromatin; IDA:ARUK-UCL.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
DR GO; GO:0016607; C:nuclear speck; IEA:UniProtKB-SubCell.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IDA:GO_Central.
DR GO; GO:0046983; F:protein dimerization activity; IEA:InterPro.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:ARUK-UCL.
DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
DR GO; GO:0006366; P:transcription by RNA polymerase II; IEA:Ensembl.
DR CDD; cd00130; PAS; 2.
DR Gene3D; 4.10.280.10; -; 1.
DR InterPro; IPR011598; bHLH_dom.
DR InterPro; IPR021537; HIF_alpha_subunit.
DR InterPro; IPR036638; HLH_DNA-bd_sf.
DR InterPro; IPR001610; PAC.
DR InterPro; IPR000014; PAS.
DR InterPro; IPR035965; PAS-like_dom_sf.
DR InterPro; IPR013767; PAS_fold.
DR InterPro; IPR013655; PAS_fold_3.
DR Pfam; PF11413; HIF-1; 1.
DR Pfam; PF00989; PAS; 1.
DR Pfam; PF08447; PAS_3; 1.
DR SMART; SM00353; HLH; 1.
DR SMART; SM00086; PAC; 1.
DR SMART; SM00091; PAS; 2.
DR SUPFAM; SSF47459; SSF47459; 1.
DR SUPFAM; SSF55785; SSF55785; 2.
DR TIGRFAMs; TIGR00229; sensory_box; 1.
DR PROSITE; PS50888; BHLH; 1.
DR PROSITE; PS50112; PAS; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Angiogenesis; Apoptosis; Cytoplasm;
KW Developmental protein; Hydroxylation; Isopeptide bond; Mitochondrion;
KW Nucleus; Reference proteome; Repeat; Repressor; Stress response;
KW Transcription; Transcription regulation; Tumor suppressor; Ubl conjugation.
FT CHAIN 1..669
FT /note="Hypoxia-inducible factor 3-alpha"
FT /id="PRO_0000284414"
FT DOMAIN 14..67
FT /note="bHLH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT DOMAIN 82..154
FT /note="PAS 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT DOMAIN 227..297
FT /note="PAS 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT REGION 1..27
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 77..100
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:Q0VBL6"
FT REGION 230..274
FT /note="Nuclear export signal"
FT /evidence="ECO:0000250|UniProtKB:Q0VBL6"
FT REGION 354..389
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 430..451
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 452..581
FT /note="ODD"
FT REGION 454..506
FT /note="NTAD"
FT REGION 523..600
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 619..669
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 414..418
FT /note="LRRLL"
FT MOTIF 490..497
FT /note="LAPYISMD"
FT COMPBIAS 10..27
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 354..378
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 573..588
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 646..669
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 492
FT /note="4-hydroxyproline"
FT /evidence="ECO:0000269|PubMed:12538644"
FT CROSSLNK 467
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:12538644"
FT CROSSLNK 570
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:12538644"
FT VAR_SEQ 1..120
FT /note="MALGLQRARSTTELRKEKSRDAARSRRSQETEVLYQLAHTLPFARGVSAHLD
FT KASIMRLTISYLRMHRLCAAGEWNQVGAGGEPLDACYLKALEGFVMVLTAEGDMAYLSE
FT NVSKHLGLS -> MRPAAGAARRPRCCTSWLTRCPSPAASAPTWTRPLSCASPSATCAC
FT TASAP (in isoform 7)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_043429"
FT VAR_SEQ 1..86
FT /note="Missing (in isoform 6)"
FT /evidence="ECO:0000305"
FT /id="VSP_024518"
FT VAR_SEQ 1..56
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_024519"
FT VAR_SEQ 1..8
FT /note="MALGLQRA -> MDWQDH (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11573933"
FT /id="VSP_024520"
FT VAR_SEQ 87..137
FT /note="ACYLKALEGFVMVLTAEGDMAYLSENVSKHLGLSQLELIGHSIFDFIHPCD
FT -> MRPAAGAARRPRCCTSWLTRCPSPAASAPTWTRPLSCASPSATCACTASAP (in
FT isoform 6)"
FT /evidence="ECO:0000305"
FT /id="VSP_024521"
FT VAR_SEQ 293..363
FT /note="LLSKGQAVTGQYRFLARSGGYLWTQTQATVVSGGRGPQSESIVCVHFLISQV
FT EETGVVLSLEQTEQHSRRP -> CMYPISPGAKPAATWPPADTRTPQLPIPQDALPPHL
FT NTSSLLPKPQGTVSFLAPSYPVPRSFSPHLPPWWP (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:16126907"
FT /id="VSP_024523"
FT VAR_SEQ 364..669
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:16126907"
FT /id="VSP_024525"
FT VAR_SEQ 611..669
FT /note="SFLLTGGPAPGSLQDPSTPLLNLNEPLGLGPSLLSPYSDEDTTQPGGPFQPR
FT AGSAQAD -> VCWGINGILWPSLPSWLKPTVL (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039, ECO:0000303|Ref.2,
FT ECO:0000303|Ref.4"
FT /id="VSP_024526"
FT VARIANT 343
FT /note="Q -> R (in dbSNP:rs3764609)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_031731"
FT VARIANT 463
FT /note="F -> L (in dbSNP:rs7253301)"
FT /id="VAR_031732"
FT MUTAGEN 467
FT /note="K->R: No loss of ubiquitination. Reduced
FT ubiquitination; when associated with R-570."
FT /evidence="ECO:0000269|PubMed:12538644"
FT MUTAGEN 492
FT /note="P->A: Reduced hydroxylation activity. Reduced
FT ubiquitination."
FT /evidence="ECO:0000269|PubMed:12538644"
FT MUTAGEN 570
FT /note="K->R: No loss of ubiquitination. Reduced
FT ubiquitination; when associated with R-467."
FT /evidence="ECO:0000269|PubMed:12538644"
FT CONFLICT 202
FT /note="A -> V (in Ref. 5; BAB55324)"
FT /evidence="ECO:0000305"
FT CONFLICT 497
FT /note="D -> G (in Ref. 5; BAB55324)"
FT /evidence="ECO:0000305"
FT STRAND 241..245
FT /evidence="ECO:0007829|PDB:4WN5"
FT STRAND 250..254
FT /evidence="ECO:0007829|PDB:4WN5"
FT HELIX 258..262
FT /evidence="ECO:0007829|PDB:4WN5"
FT HELIX 266..269
FT /evidence="ECO:0007829|PDB:4WN5"
FT HELIX 274..277
FT /evidence="ECO:0007829|PDB:4WN5"
FT TURN 280..282
FT /evidence="ECO:0007829|PDB:4WN5"
FT HELIX 283..296
FT /evidence="ECO:0007829|PDB:4WN5"
FT STRAND 297..300
FT /evidence="ECO:0007829|PDB:4WN5"
FT STRAND 304..307
FT /evidence="ECO:0007829|PDB:4WN5"
FT STRAND 313..323
FT /evidence="ECO:0007829|PDB:4WN5"
FT HELIX 329..331
FT /evidence="ECO:0007829|PDB:4WN5"
FT STRAND 333..342
FT /evidence="ECO:0007829|PDB:4WN5"
SQ SEQUENCE 669 AA; 72433 MW; 81C4C84517000DE2 CRC64;
MALGLQRARS TTELRKEKSR DAARSRRSQE TEVLYQLAHT LPFARGVSAH LDKASIMRLT
ISYLRMHRLC AAGEWNQVGA GGEPLDACYL KALEGFVMVL TAEGDMAYLS ENVSKHLGLS
QLELIGHSIF DFIHPCDQEE LQDALTPQQT LSRRKVEAPT ERCFSLRMKS TLTSRGRTLN
LKAATWKVLN CSGHMRAYKP PAQTSPAGSP DSEPPLQCLV LICEAIPHPG SLEPPLGRGA
FLSRHSLDMK FTYCDDRIAE VAGYSPDDLI GCSAYEYIHA LDSDAVSKSI HTLLSKGQAV
TGQYRFLARS GGYLWTQTQA TVVSGGRGPQ SESIVCVHFL ISQVEETGVV LSLEQTEQHS
RRPIQRGAPS QKDTPNPGDS LDTPGPRILA FLHPPSLSEA ALAADPRRFC SPDLRRLLGP
ILDGASVAAT PSTPLATRHP QSPLSADLPD ELPVGTENVH RLFTSGKDTE AVETDLDIAQ
DADALDLEML APYISMDDDF QLNASEQLPR AYHRPLGAVP RPRARSFHGL SPPALEPSLL
PRWGSDPRLS CSSPSRGDPS ASSPMAGARK RTLAQSSEDE DEGVELLGVR PPKRSPSPEH
ENFLLFPLSL SFLLTGGPAP GSLQDPSTPL LNLNEPLGLG PSLLSPYSDE DTTQPGGPFQ
PRAGSAQAD
