HIF1A

Subunidad alfa del factor 1 inducible por hipoxia
	; Estructura tridimensional de la proteína HIF1A.
Estructuras disponibles
PDB	Buscar ortólogos: PDBe, RCSB Lista de códigos PDB 1H2K , 1H2L , 1H2M , 1L3E , 1L8C , 1LM8 , 1LQB , 2ILM , 3HQR , 3HQU , 4AJY , 4H6J
Identificadores
Símbolos	HIF1A (HGNC: 4910) HIF-1alpha; HIF1-ALPHA; MOP1; PASD8
Identificadores; externos	OMIM: 603348 ; HomoloGene: 1171 ; EBI: HIF1A; GeneCards: Gen HIF1A; UniProt: HIF1A;
Locus	Cr. 14 q23.2
	Referencias: AmiGO / QuickGO
Patrón de expresión de ARNm
	Más información
Ortólogos
Humano	Ratón
3091	15251
Véase HS	Véase MM
Q16665	Q61221
NM_001243084	NM_010431
NP_001230013	NP_034561
Cr. 14:; 62.16 – 62.21 Mb	Cr. 12:; 73.9 – 73.95 Mb
;

La subunidad alfa del factor 1 inducible por hipoxia (HIF1A) es una proteína codificada en humanos por el gen HIF1A.[1][2] Se han descrito dos variantes transcripcionales que codifican diferentes isoformas de la proteína.[3]

Estructura

HIF1 es un heterodímero con un dominio hélice-bucle-hélice básico[4] compuesto por HIF1A, referida como subunidad alfa (esta proteína), y el translocador nuclear del receptor de aril hidrocaruros (ARNT), referido como la subunidad beta.

Función

HIF1A es un factor de transcripción con dominios HLH-PAS encontrado en células de mamíferos que crecen en concentraciones bajas de oxígeno. Juega un papel esencial en la respuesta celular y sistémica a la hipoxia.[5] HIF1A es una de las clases de factores inducibles por hipoxia, una familia que incluye HIF1A, HIF2A y HIF3A.

Regulación

La abundancia de HIF1A (y su actividad subsecuente) es regulada a nivel transcripcional a través de NF-κB.[6] Además, la actividad coordinada de las prolil hidroxilasas (PHDs) mantienen el balance apropiado de proteína HIF1A en la fase postraduccional.[7]

Importancia clínica

La sobre-expresión de un transcrito natural antisentido (aHIF) de este gen es asociada con el desarrollo de carcinoma renal no papilar.[8]

Interacciones

La proteína HIF1A ha demostrado ser capaz de interaccionar con:

PSMA7[9]
NR4A[10]
STAT3[11]
CREBBP[12][13][14]
ARNTL[15]
ARNT[2][16]
p53[17][18][19][20]
EP300[21][22]
HIF1AN[23]
Mdm2[17][18]
Supresor tumoral Von Hippel-Lindau[10][11][14][23][24][25][26][27][28][29]
Ubiquitina C[10][14][29]

Véase también

Referencias

Semenza GL, Rue EA, Iyer NV, Pang MG, Kearns WG (junio de 1996). «Assignment of the hypoxia-inducible factor 1alpha gene to a region of conserved synteny on mouse chromosome 12 and human chromosome 14q». Genomics 34 (3): 437-9. PMID 8786149. doi:10.1006/geno.1996.0311.
Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, Bradfield CA (marzo de 1997). «Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway». J. Biol. Chem. 272 (13): 8581-93. PMID 9079689. doi:10.1074/jbc.272.13.8581.
«Entrez Gene: HIF1A hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)».
Wang FS, Wang CJ, Chen YJ, et al. (marzo de 2004). «Ras induction of superoxide activates ERK-dependent angiogenic transcription factor HIF-1alpha and VEGF-A expression in shock wave-stimulated osteoblasts». J. Biol. Chem. 279 (11): 10331-7. PMID 14681237. doi:10.1074/jbc.M308013200.
Ratcliffe PJ (2003). «From erythropoietin to oxygen: hypoxia-inducible factor hydroxylases and the hypoxia signal pathway.». Blood Purif. 20 (5): 445-50. PMID 12207089. doi:10.1159/000065201.
van Uden P, Kenneth NS, Rocha S (2008). «Regulation of hypoxia-inducible factor-1alpha by NF-kappaB». Biochem J. 412 (3): 477-484. PMID 18393939. doi:10.1042/BJ20080476.
Semenza GL (agosto de 2004). «Hydroxylation of HIF-1: oxygen sensing at the molecular level». Physiology (Bethesda) 19: 176-82. PMID 15304631. doi:10.1152/physiol.00001.2004.
Quintero M, Mackenzie N, Brennan PA (junio de 2004). «Hypoxia-inducible factor 1 (HIF-1) in cancer». Eur J Surg Oncol 30 (5): 465-8. PMID 15135470. doi:10.1016/j.ejso.2004.03.008.
Cho, S; Choi Y J, Kim J M, Jeong S T, Kim J H, Kim S H, Ryu S E (Jun. de 2001). «Binding and regulation of HIF-1alpha by a subunit of the proteasome complex, PSMA7». FEBS Lett. (Netherlands) 498 (1): 62-6. ISSN 0014-5793. PMID 11389899.
Kim, Bu Yeon; Kim Hyungsoo, Cho Eun Jung, Youn Hong Duk (Feb. de 2008). «Nur77 upregulates HIF-alpha by inhibiting pVHL-mediated degradation». Exp. Mol. Med. (Korea (South)) 40 (1): 71-83. ISSN 1226-3613. PMID 18305400.
Jung, Joo Eun; Kim Hong Sook, Lee Chang Seok, Shin Yong Jae, Kim Yong Nyun, Kang Gyeong Hoon, Kim Tae You, Juhnn Yong Sung, Kim Sung Joon, Park Jong Wan, Ye Sang Kyu, Chung Myung Hee (Oct. de 2008). «STAT3 inhibits the degradation of HIF-1alpha by pVHL-mediated ubiquitination». Exp. Mol. Med. (Korea (South)) 40 (5): 479-85. ISSN 1226-3613. PMID 18985005.
Ema, M; Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K, Poellinger L, Fujii-Kuriyama Y (Apr. de 1999). «Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300». EMBO J. (ENGLAND) 18 (7): 1905-14. ISSN 0261-4189. PMID 10202154. doi:10.1093/emboj/18.7.1905.
Bhattacharya, S; Michels C L, Leung M K, Arany Z P, Kung A L, Livingston D M (Jan. de 1999). «Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1». Genes Dev. (UNITED STATES) 13 (1): 64-75. ISSN 0890-9369. PMID 9887100.
Park, Young-Kwon; Ahn Dae-Ro, Oh Myoungsuk, Lee Taekyoung, Yang Eun Gyeong, Son Miwon, Park Hyunsung (Jul. de 2008). «Nitric oxide donor, (+/-)-S-nitroso-N-acetylpenicillamine, stabilizes transactive hypoxia-inducible factor-1alpha by inhibiting von Hippel-Lindau recruitment and asparagine hydroxylation». Mol. Pharmacol. (United States) 74 (1): 236-45. PMID 18426857. doi:10.1124/mol.108.045278.
Hogenesch, J B; Gu Y Z, Jain S, Bradfield C A (mayo. de 1998). «The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors». Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 95 (10): 5474-9. ISSN 0027-8424. PMID 9576906.
Woods, Susan L; Whitelaw Murray L (Mar. de 2002). «Differential activities of murine single minded 1 (SIM1) and SIM2 on a hypoxic response element. Cross-talk between basic helix-loop-helix/per-Arnt-Sim homology transcription factors». J. Biol. Chem. (United States) 277 (12): 10236-43. ISSN 0021-9258. PMID 11782478. doi:10.1074/jbc.M110752200.
Chen, Delin; Li Muyang, Luo Jianyuan, Gu Wei (Apr. de 2003). «Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function». J. Biol. Chem. (United States) 278 (16): 13595-8. ISSN 0021-9258. PMID 12606552. doi:10.1074/jbc.C200694200.
Ravi, R; Mookerjee B, Bhujwalla Z M, Sutter C H, Artemov D, Zeng Q, Dillehay L E, Madan A, Semenza G L, Bedi A (Jan. de 2000). «Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha». Genes Dev. (UNITED STATES) 14 (1): 34-44. ISSN 0890-9369. PMID 10640274.
Hansson, Lars O; Friedler Assaf, Freund Stefan, Rudiger Stefan, Fersht Alan R (Aug. de 2002). «Two sequence motifs from HIF-1alpha bind to the DNA-binding site of p53». Proc. Natl. Acad. Sci. U.S.A. (United States) 99 (16): 10305-9. ISSN 0027-8424. PMID 12124396. doi:10.1073/pnas.122347199.
An, W G; Kanekal M, Simon M C, Maltepe E, Blagosklonny M V, Neckers L M (Mar. de 1998). «Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha». Nature (ENGLAND) 392 (6674): 405-8. ISSN 0028-0836. PMID 9537326. doi:10.1038/32925.
Lando, David; Peet Daniel J, Whelan Dean A, Gorman Jeffrey J, Whitelaw Murray L (Feb. de 2002). «Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch». Science (United States) 295 (5556): 858-61. PMID 11823627. doi:10.1126/science.1068592.
Freedman, Steven J; Sun Zhen-Yu J, Poy Florence, Kung Andrew L, Livingston David M, Wagner Gerhard, Eck Michael J (Apr. de 2002). «Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1 alpha». Proc. Natl. Acad. Sci. U.S.A. (United States) 99 (8): 5367-72. ISSN 0027-8424. PMID 11959990. doi:10.1073/pnas.082117899.
Mahon, P C; Hirota K, Semenza G L (Oct. de 2001). «FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity». Genes Dev. (United States) 15 (20): 2675-86. ISSN 0890-9369. PMID 11641274. doi:10.1101/gad.924501.
Corn, Paul G; McDonald E Robert, Herman James G, El-Deiry Wafik S (Nov. de 2003). «Tat-binding protein-1, a component of the 26S proteasome, contributes to the E3 ubiquitin ligase function of the von Hippel-Lindau protein». Nat. Genet. (United States) 35 (3): 229-37. ISSN 1061-4036. PMID 14556007. doi:10.1038/ng1254.
Li, Zaibo; Wang Dakun, Na Xi, Schoen Susan R, Messing Edward M, Wu Guan (Apr. de 2003). «The VHL protein recruits a novel KRAB-A domain protein to repress HIF-1alpha transcriptional activity». EMBO J. (England) 22 (8): 1857-67. ISSN 0261-4189. PMID 12682018. doi:10.1093/emboj/cdg173.
Tanimoto, K; Makino Y; Pereira T; Poellinger L (Aug. de 2000). «Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein». EMBO J. (ENGLAND) 19 (16): 4298-309. ISSN 0261-4189. PMID 10944113. doi:10.1093/emboj/19.16.4298.
Min, Jung-Hyun; Yang Haifeng, Ivan Mircea, Gertler Frank, Kaelin William G, Pavletich Nikola P (Jun. de 2002). «Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling». Science (United States) 296 (5574): 1886-9. PMID 12004076. doi:10.1126/science.1073440.
Yu, F; White S B, Zhao Q, Lee F S (Aug. de 2001). «HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation». PNAS (United States) 98 (17): 9630-5. ISSN 0027-8424. PMID 11504942. doi:10.1073/pnas.181341498. Texto «Proc. Natl. Acad. Sci. U.S.A. » ignorado (ayuda)
André, Helder; Pereira Teresa S (Oct. de 2008). «Identification of an alternative mechanism of degradation of the hypoxia-inducible factor-1alpha». J. Biol. Chem. (United States) 283 (43): 29375-84. ISSN 0021-9258. PMID 18694926. doi:10.1074/jbc.M805919200.

Datos: Q20970095

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[pmid8786149-1] Semenza GL, Rue EA, Iyer NV, Pang MG, Kearns WG (junio de 1996). «Assignment of the hypoxia-inducible factor 1alpha gene to a region of conserved synteny on mouse chromosome 12 and human chromosome 14q». Genomics 34 (3): 437-9. PMID 8786149. doi:10.1006/geno.1996.0311.

[pmid9079689-2] Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, Bradfield CA (marzo de 1997). «Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway». J. Biol. Chem. 272 (13): 8581-93. PMID 9079689. doi:10.1074/jbc.272.13.8581.

[3] «Entrez Gene: HIF1A hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)».

[4] Wang FS, Wang CJ, Chen YJ, et al. (marzo de 2004). «Ras induction of superoxide activates ERK-dependent angiogenic transcription factor HIF-1alpha and VEGF-A expression in shock wave-stimulated osteoblasts». J. Biol. Chem. 279 (11): 10331-7. PMID 14681237. doi:10.1074/jbc.M308013200.

[5] Ratcliffe PJ (2003). «From erythropoietin to oxygen: hypoxia-inducible factor hydroxylases and the hypoxia signal pathway.». Blood Purif. 20 (5): 445-50. PMID 12207089. doi:10.1159/000065201.

[pmid18393939-6] van Uden P, Kenneth NS, Rocha S (2008). «Regulation of hypoxia-inducible factor-1alpha by NF-kappaB». Biochem J. 412 (3): 477-484. PMID 18393939. doi:10.1042/BJ20080476.

[pmid15304631-7] Semenza GL (agosto de 2004). «Hydroxylation of HIF-1: oxygen sensing at the molecular level». Physiology (Bethesda) 19: 176-82. PMID 15304631. doi:10.1152/physiol.00001.2004.

[pmid15135470-8] Quintero M, Mackenzie N, Brennan PA (junio de 2004). «Hypoxia-inducible factor 1 (HIF-1) in cancer». Eur J Surg Oncol 30 (5): 465-8. PMID 15135470. doi:10.1016/j.ejso.2004.03.008.

[pmid11389899-9] Cho, S; Choi Y J, Kim J M, Jeong S T, Kim J H, Kim S H, Ryu S E (Jun. de 2001). «Binding and regulation of HIF-1alpha by a subunit of the proteasome complex, PSMA7». FEBS Lett. (Netherlands) 498 (1): 62-6. ISSN 0014-5793. PMID 11389899.

[pmid18305400-10] Kim, Bu Yeon; Kim Hyungsoo, Cho Eun Jung, Youn Hong Duk (Feb. de 2008). «Nur77 upregulates HIF-alpha by inhibiting pVHL-mediated degradation». Exp. Mol. Med. (Korea (South)) 40 (1): 71-83. ISSN 1226-3613. PMID 18305400.

[pmid18985005-11] Jung, Joo Eun; Kim Hong Sook, Lee Chang Seok, Shin Yong Jae, Kim Yong Nyun, Kang Gyeong Hoon, Kim Tae You, Juhnn Yong Sung, Kim Sung Joon, Park Jong Wan, Ye Sang Kyu, Chung Myung Hee (Oct. de 2008). «STAT3 inhibits the degradation of HIF-1alpha by pVHL-mediated ubiquitination». Exp. Mol. Med. (Korea (South)) 40 (5): 479-85. ISSN 1226-3613. PMID 18985005.

[pmid10202154-12] Ema, M; Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K, Poellinger L, Fujii-Kuriyama Y (Apr. de 1999). «Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300». EMBO J. (ENGLAND) 18 (7): 1905-14. ISSN 0261-4189. PMID 10202154. doi:10.1093/emboj/18.7.1905.

[pmid9887100-13] Bhattacharya, S; Michels C L, Leung M K, Arany Z P, Kung A L, Livingston D M (Jan. de 1999). «Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1». Genes Dev. (UNITED STATES) 13 (1): 64-75. ISSN 0890-9369. PMID 9887100.

[pmid18426857-14] Park, Young-Kwon; Ahn Dae-Ro, Oh Myoungsuk, Lee Taekyoung, Yang Eun Gyeong, Son Miwon, Park Hyunsung (Jul. de 2008). «Nitric oxide donor, (+/-)-S-nitroso-N-acetylpenicillamine, stabilizes transactive hypoxia-inducible factor-1alpha by inhibiting von Hippel-Lindau recruitment and asparagine hydroxylation». Mol. Pharmacol. (United States) 74 (1): 236-45. PMID 18426857. doi:10.1124/mol.108.045278.

[pmid9576906-15] Hogenesch, J B; Gu Y Z, Jain S, Bradfield C A (mayo. de 1998). «The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors». Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 95 (10): 5474-9. ISSN 0027-8424. PMID 9576906.

[pmid11782478-16] Woods, Susan L; Whitelaw Murray L (Mar. de 2002). «Differential activities of murine single minded 1 (SIM1) and SIM2 on a hypoxic response element. Cross-talk between basic helix-loop-helix/per-Arnt-Sim homology transcription factors». J. Biol. Chem. (United States) 277 (12): 10236-43. ISSN 0021-9258. PMID 11782478. doi:10.1074/jbc.M110752200.

[pmid12606552-17] Chen, Delin; Li Muyang, Luo Jianyuan, Gu Wei (Apr. de 2003). «Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function». J. Biol. Chem. (United States) 278 (16): 13595-8. ISSN 0021-9258. PMID 12606552. doi:10.1074/jbc.C200694200.

[pmid10640274-18] Ravi, R; Mookerjee B, Bhujwalla Z M, Sutter C H, Artemov D, Zeng Q, Dillehay L E, Madan A, Semenza G L, Bedi A (Jan. de 2000). «Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha». Genes Dev. (UNITED STATES) 14 (1): 34-44. ISSN 0890-9369. PMID 10640274.

[pmid12124396-19] Hansson, Lars O; Friedler Assaf, Freund Stefan, Rudiger Stefan, Fersht Alan R (Aug. de 2002). «Two sequence motifs from HIF-1alpha bind to the DNA-binding site of p53». Proc. Natl. Acad. Sci. U.S.A. (United States) 99 (16): 10305-9. ISSN 0027-8424. PMID 12124396. doi:10.1073/pnas.122347199.

[pmid9537326-20] An, W G; Kanekal M, Simon M C, Maltepe E, Blagosklonny M V, Neckers L M (Mar. de 1998). «Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha». Nature (ENGLAND) 392 (6674): 405-8. ISSN 0028-0836. PMID 9537326. doi:10.1038/32925.

[pmid11823643-21] Lando, David; Peet Daniel J, Whelan Dean A, Gorman Jeffrey J, Whitelaw Murray L (Feb. de 2002). «Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch». Science (United States) 295 (5556): 858-61. PMID 11823627. doi:10.1126/science.1068592.

[pmid11959990-22] Freedman, Steven J; Sun Zhen-Yu J, Poy Florence, Kung Andrew L, Livingston David M, Wagner Gerhard, Eck Michael J (Apr. de 2002). «Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1 alpha». Proc. Natl. Acad. Sci. U.S.A. (United States) 99 (8): 5367-72. ISSN 0027-8424. PMID 11959990. doi:10.1073/pnas.082117899.

[pmid11641274-23] Mahon, P C; Hirota K, Semenza G L (Oct. de 2001). «FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity». Genes Dev. (United States) 15 (20): 2675-86. ISSN 0890-9369. PMID 11641274. doi:10.1101/gad.924501.

[pmid14556007-24] Corn, Paul G; McDonald E Robert, Herman James G, El-Deiry Wafik S (Nov. de 2003). «Tat-binding protein-1, a component of the 26S proteasome, contributes to the E3 ubiquitin ligase function of the von Hippel-Lindau protein». Nat. Genet. (United States) 35 (3): 229-37. ISSN 1061-4036. PMID 14556007. doi:10.1038/ng1254.

[pmid12682018-25] Li, Zaibo; Wang Dakun, Na Xi, Schoen Susan R, Messing Edward M, Wu Guan (Apr. de 2003). «The VHL protein recruits a novel KRAB-A domain protein to repress HIF-1alpha transcriptional activity». EMBO J. (England) 22 (8): 1857-67. ISSN 0261-4189. PMID 12682018. doi:10.1093/emboj/cdg173.

[pmid10944113-26] Tanimoto, K; Makino Y; Pereira T; Poellinger L (Aug. de 2000). «Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein». EMBO J. (ENGLAND) 19 (16): 4298-309. ISSN 0261-4189. PMID 10944113. doi:10.1093/emboj/19.16.4298.

[pmid12004076-27] Min, Jung-Hyun; Yang Haifeng, Ivan Mircea, Gertler Frank, Kaelin William G, Pavletich Nikola P (Jun. de 2002). «Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling». Science (United States) 296 (5574): 1886-9. PMID 12004076. doi:10.1126/science.1073440.

[pmid11504942-28] Yu, F; White S B, Zhao Q, Lee F S (Aug. de 2001). «HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation». PNAS (United States) 98 (17): 9630-5. ISSN 0027-8424. PMID 11504942. doi:10.1073/pnas.181341498. Texto «Proc. Natl. Acad. Sci. U.S.A. » ignorado (ayuda)

[pmid18694926-29] André, Helder; Pereira Teresa S (Oct. de 2008). «Identification of an alternative mechanism of degradation of the hypoxia-inducible factor-1alpha». J. Biol. Chem. (United States) 283 (43): 29375-84. ISSN 0021-9258. PMID 18694926. doi:10.1074/jbc.M805919200.