Key points are not available for this paper at this time.
Cell adaptation to hypoxia is partially accomplished by hypoxia-inducible transcription factor-1 (HIF-1). Here we report the hypoxia-independent up-regulation of HIF-1α subunit in antigen receptor-activated T cells. This is explained by a selective up-regulation of alternatively spliced mRNA isoform I.1 that encodes the HIF-1α protein without the first 12 N-terminal amino acids. We show that both short (I.1) and long (I.2) HIF-1α isoforms display similar DNA binding and transcriptional activities. Major differences were observed between these two HIF-1α isoforms in their expression patterns with respect to the resting and activated T lymphocytes in hypoxic and normoxic conditions. The T cell antigen receptor (TCR)-triggered activation of normal ex vivo T cells and differentiated T cells results in up-regulation of expression of I.1 isoform of HIF-1α mRNA without an effect on constitutive I.2 HIF-1α mRNA expression. The accumulation of I.1 HIF-1α mRNA isoform in T lymphocytes is also demonstrated during cytokine-mediated inflammation in vivo, suggesting a physiological role of short HIF-1α isoform in activated lymphocytes. The TCR-triggered, protein kinase C and Ca2+/calcineurin-mediated HIF-1α I.1 mRNA induction is protein synthesis-independent, suggesting that the HIF-1α I.1 gene is expressed as an immediate early response gene. Therefore, these data predict a different physiological role of short and long isoforms of HIF-1α in resting and activated cells. Cell adaptation to hypoxia is partially accomplished by hypoxia-inducible transcription factor-1 (HIF-1). Here we report the hypoxia-independent up-regulation of HIF-1α subunit in antigen receptor-activated T cells. This is explained by a selective up-regulation of alternatively spliced mRNA isoform I.1 that encodes the HIF-1α protein without the first 12 N-terminal amino acids. We show that both short (I.1) and long (I.2) HIF-1α isoforms display similar DNA binding and transcriptional activities. Major differences were observed between these two HIF-1α isoforms in their expression patterns with respect to the resting and activated T lymphocytes in hypoxic and normoxic conditions. The T cell antigen receptor (TCR)-triggered activation of normal ex vivo T cells and differentiated T cells results in up-regulation of expression of I.1 isoform of HIF-1α mRNA without an effect on constitutive I.2 HIF-1α mRNA expression. The accumulation of I.1 HIF-1α mRNA isoform in T lymphocytes is also demonstrated during cytokine-mediated inflammation in vivo, suggesting a physiological role of short HIF-1α isoform in activated lymphocytes. The TCR-triggered, protein kinase C and Ca2+/calcineurin-mediated HIF-1α I.1 mRNA induction is protein synthesis-independent, suggesting that the HIF-1α I.1 gene is expressed as an immediate early response gene. Therefore, these data predict a different physiological role of short and long isoforms of HIF-1α in resting and activated cells. hypoxia-inducible factor vascular endothelial growth factor inducible nitric-oxide synthase hypoxia response element pVHL, von Hippel-Lindau protein reverse transcription T cell antigen receptor concanavalin A monoclonal antibody 4-morpholineethanesulfonic acid 2-bis(2-hydroxyethyl)amino-2-(hydroxymethyl)propane-1,3-diol Immune cells are exposed to different oxygen tensions, including hypoxia, as they develop, migrate, and function in primary, secondary, and tertiary lymphoid organs with different infrastructure, vasculature, and oxygen supply (1Picker L.J. Siegelman M.H. Paul W.E. Fundamental Immunology. Lippincott-Raven Publishers, Philadelphia1999: 479-533Google Scholar, 2Westermann J. Bode U. Immunol. Today. 1999; 20: 302-306Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). Hypoxic extracellular environments were demonstrated in some normal tissues (3Loeffler D.A. Keng P.C. Baggs R.B. Lord E.M. Int. J. Cancer. 1990; 45: 462-467Crossref PubMed Scopus (36) Google Scholar, 4Dewhirst M.W. Semin. Radiat. Oncol. 1998; 8: 143-150Crossref PubMed Scopus (146) Google Scholar) and during chronic inflammatory and malignant diseases (5Jelkmann W. J. Interferon Cytokine Res. 1998; 18: 555-557Crossref PubMed Scopus (335) Google Scholar, 6Van Belle H. Goossens F. Wynants J. Am. J. Pathol. 1987; 252: H886-H893Google Scholar, 7Matherne G.P. Headrick J.P. Coleman S.D. Berne R.M. Pediatr. Res. 1990; 28: 348-353Crossref PubMed Scopus (54) Google Scholar, 8Vaupel P.W. Frinak S. Bicher H.I. Cancer Res. 1981; 41: 2008-2013PubMed Google Scholar, 9Vaupel P. Kalinowski F. Okunieff P. Cancer Res. 1989; 49: 6449-6465PubMed Google Scholar, 10Hoskin D.W. Reynolds T. Blay J. Int. J. Cancer. 1994; 59: 854-855Crossref PubMed Scopus (70) Google Scholar). The mechanisms of lymphocyte adaptation to hypoxia are likely to exist under such conditions. Cell adaptation to hypoxia is partially accomplished by the transcriptional activity of hypoxia-inducible factor-1 (HIF-1).1 HIF-1 is a basic helix-loop-helix/Per-ARNT-Sim protein consisting of HIF-1α and HIF-1β subunits (11Wang G.L. Semenza G.L. J. Biol. Chem. 1995; 270: 1230-1237Abstract Full Text Full Text PDF PubMed Scopus (1765) Google Scholar, 12Wang G.L. Jiang B.H. Rue E.A. Semenza G.L. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5510-5514Crossref PubMed Scopus (5208) Google Scholar). The HIF-1β subunit is also known as aryl hydrocarbon receptor nuclear translocator (ARNT) and serves as a heterodimerization partner for other transcription factors (13Rowlands J.C. Gustafsson J.A. Crit. Rev. Toxicol. 1997; 27: 109-134Crossref PubMed Scopus (442) Google Scholar, 14Sogawa K. Fujii-Kuriyama Y. J. Biochem. (Tokyo). 1997; 122: 1075-1079Crossref PubMed Scopus (181) Google Scholar, 15Ema M. Morita M. Ikawa S. Tanaka M. Matsuda Y. Gotoh O. Saijoh Y. Fujii H. Hamada H. Kikuchi Y. Fujii-Kuriyama Y. Mol. Cell. Biol. 1996; 16: 5865-5875Crossref PubMed Scopus (138) Google Scholar, 16Whitmore D. Sassone-Corsi P. Foulkes N.S. Curr. Opin. Neurobiol. 1998; 8: 635-641Crossref PubMed Scopus (25) Google Scholar, 17Zheng B. Larkin D.W. Albrecht U. Sun Z.S. Sage M. Eichele G. Lee C.C. Bradley A. Nature. 1999; 400: 169-173Crossref PubMed Scopus (21) Google Scholar). HIF-1 activates the transcription of genes required for glucose metabolism, erythropoiesis, vascularization, and cell proliferation by binding to cis-acting hypoxia response element (HRE) (18Semenza G.L. Agani F. Booth G. Forsythe J. Iyer N.V. Jiang B.-H. Leung S. Roe R. Wiener C. Yu A. Kidney Int. 1997; 51: 553-555Abstract Full Text PDF PubMed Scopus (271) Google Scholar, 19Wenger R.H. Gassmann M. Biol. Chem. 1997; 378: 609-616PubMed Google Scholar, 20Semenza G.L. Genes Dev. 2000; 14: 1983-1991Crossref PubMed Google Scholar, 21Semenza G.L. Curr. Opin. Gene Dev. 1998; 8: 588-594Crossref PubMed Scopus (946) Google Scholar, 22Iyer N.V. Kotch L.E. Agani F. Leung S.W. Laughner E. Wenger R.H. Gassmann M. Gearhart J.D. Lawler A.M. Yu A.Y. Semenza G.L. Genes Dev. 1998; 12: 149-162Crossref PubMed Scopus (2103) Google Scholar). The HIF-1α subunit may also affect cell metabolism and signaling by its ability to directly interact with other proteins such as p53 (23An W.G. Kanekal M. Simon M.C. Maltepe E. Blagosklonny M.V. Neckers L.M. Nature. 1998; 392: 405-408Crossref PubMed Scopus (660) Google Scholar). Multiple roles of HIF-1α as transcriptional factor and in protein-protein interactions complicate the understanding of its role in vivo. Possible clues are expected to be provided by studies of regulation of HIF-1α mRNA and protein expression. Oxygen-sensing mechanisms and the subsequent regulation of HIF-1 expression are the subject of intensive investigations. It was shown that HIF-1α, but not HIF-1β, expression is significantly enhanced by hypoxia (12Wang G.L. Jiang B.H. Rue E.A. Semenza G.L. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5510-5514Crossref PubMed Scopus (5208) Google Scholar, 24Huang L.E. Arany Z. Livingston D.M. Bunn H.F. J. Biol. Chem. 1996; 271: 32253-32259Abstract Full Text Full Text PDF PubMed Scopus (1035) Google Scholar, 25Jiang B.-H. Semenza G.L. Bauer C. Marti H.H. Am. J. Physiol. 1996; 271: C1172-C1180Crossref PubMed Google Scholar). It is believed that the regulation of HIF-1α expression occurs mostly on post-translational level (19Wenger R.H. Gassmann M. Biol. Chem. 1997; 378: 609-616PubMed Google Scholar). HIF-1α mRNA is expressed in cells of oxygen R.H. A. Gassmann M. Marti H.H. Kidney Int. 1997; 51: Full Text PDF PubMed Scopus Google R.H. A. Marti H.H. Gassmann M. Biochem. Res. 1996; PubMed Scopus Google but its expression is by hypoxia in vivo M. Yu A.Y. Semenza G.L. J. 1999; PubMed Scopus Google Scholar, Booth G. Semenza G.L. Biochem. Res. 1996; PubMed Scopus Google Scholar, A.Y. Wiener K. Semenza G.L. Am. J. Physiol. 1998; PubMed Google Scholar). role in of HIF-1α expression. oxygen tensions, HIF-1α is for by an the von Hippel-Lindau protein P. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. L.E. W.G. Cell Biol. 2000; PubMed Scopus Google Scholar). to a to the in the of HIF-1α J. Biochem. Res. 1999; PubMed Scopus Google Scholar) that results in a subsequent of HIF-1α the S. J. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, L.E. J. M. Bunn H.F. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). We were to by of oxygen induction of HIF-1α by E. J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Google Scholar) and P. E.A. J. E. Biochem. J. 2000; PubMed Scopus Google Scholar) as as by studies of HIF-1α expression in activated T lymphocytes. and M. in It was also to the of expression of two HIF-1α mRNA two first I.1 and I.2 R.H. A. P. P. Gassmann M. J. Biochem. 1997; PubMed Scopus Google Scholar, R.H. A. P. Gassmann M. 1998; PubMed Google Scholar). The I.1 mRNA encodes a is expected to be 12 N-terminal amino acid HIF-1α I.2 in of these HIF-1α isoforms A. G. Wenger R.H. Gassmann M. 2000; PubMed Scopus Google Scholar). isoform The of these two mRNA isoforms in cells and patterns of expression of HIF-1α I.1 mRNA in resting differentiated cells are not HIF-1α I.2 mRNA is expressed a gene in tissues in an oxygen I.1 mRNA a expression R.H. A. P. Gassmann M. 1998; PubMed Google Scholar). studies of expression of these two HIF-1α mRNA isoforms may to to roles of HIF-1α as a transcription factor and in protein-protein interactions provided that the expression of short and long of HIF-1α is in we HIF-1α mRNA is expressed in ex vivo T ex vivo activated T differentiated T and resting activated T cells by of the provided by We report that activation of T lymphocytes results in up-regulation of the I.1 isoform of HIF-1α mRNA without an effect on I.2 mRNA expression. The expression of I.1 HIF-1α mRNA a of immediate early response regulation and of these two isoforms of HIF-1α proteins in resting and activated cells. T cells and were in with and amino and were in with and cell were T cells were a of and to cells on an the cells were in was cell oxygen but not in the for oxygen to be oxygen were and to for with a and were in a oxygen as in the and cells were of T cells in to J. H. J. Paul W.E. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar, and they were provided by J. of The cells were in with of the in HIF-1α mRNA regulation were of cells with were as A and T cells were activated by and for as S. M. Int. Immunol. 1999; PubMed Scopus Google Scholar). were with concanavalin A in were and T cells were as was the to the of and in the were to the were and in with by were for and to was as (12Wang G.L. Jiang B.H. Rue E.A. Semenza G.L. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5510-5514Crossref PubMed Scopus (5208) Google Scholar) that were was to cells to the was the J. T. A Scholar) of with the mRNA HIF-1α was a HIF-1α The was The of HIF-1α with HIF-1α was to be for of the was reverse was with and and was of the in the HIF-1α The HIF-1α was HIF-1α I.1 and I.2 were by and and was on activated cells. were with in the of and in The were also in for of I.1 I.2 mRNA in was by on and A was with and and in for was by and was with and and in by up-regulation of HIF-1α I.1 mRNA T cell for I.1 and I.2 isoforms of HIF-1α mRNA T cells and cells. were with without for of for for HIF-1α I.1 and I.2 mRNA for HIF-1α I.1 mRNA T cells and cells. were activated as The of the and are by the with are is the The of HIF-1α mRNA cells is for the of were for mRNA expression. for HIF-1α I.2 mRNA T cells and cells. were as The of the and are by the The of was for T cell up-regulation of of concanavalin A. were with concanavalin A and and were by and were for HIF-1α I.1 mRNA T cells. T lymphocytes vivo by as under are The of HIF-1α mRNA T cells is as were for mRNA was with to the was in and an was of was and of was to reverse transcription in the as for was the by with The first was on of the with to the the was to a of The was DNA under for in a that of the and of DNA the in the and a and a HIF-1α of was in a and by The of was with The of were for differences in between of mRNA a The of mRNA as an in studies of activated T lymphocytes was in by M. S. P. M.V. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). of mRNA was by the the in a with of the of DNA were in by of was as in A. G. Wenger R.H. Gassmann M. 2000; PubMed Scopus Google Scholar). of R. in and of O. were for transcription in of and by were for in with without of in and of the HIF-1α isoforms were for the of for of was to the gene and binding to a of The but was as a in of the were with the isoform was by in expression of the I.1 isoform was by of to amino acid I.2 HIF-1α was provided by G. Semenza and was a O. of was provided by M. Blagosklonny of were in the were in in the to the The of were of of of the of The of was to with was and cells were for an activity was the to the studies of T cell under hypoxic HIF-1α protein up-regulation in activated T lymphocytes under normoxic T lymphocytes are not to HIF-1α This in normoxic in different cells with E. J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Google Scholar) P. E.A. J. E. Biochem. J. 2000; PubMed Scopus Google Scholar). We studies of HIF-1α regulation in activated T HIF-1α transcriptional and proteins G.L. Crit. Rev. Biochem. Mol. Biol. 2000; PubMed Scopus Google Scholar). of HIF-1α protein and HIF-1α mRNA in activated T cells is demonstrated by and of T cells their with oxygen of HIF-1α mRNA in activated T cells was HIF-1α regulation was known to be on a post-translational level (19Wenger R.H. Gassmann M. Biol. Chem. 1997; 378: 609-616PubMed Google Scholar). mRNA expression studies by of HIF-1α mRNA in T lymphocytes were by the of the of cells and of HIF-1α mRNA by This of of cells in different T cells ex vivo and in and the of the to the of HIF-1α mRNA We that HIF-1α mRNA expression is in T cells as with with a in HIF-1α mRNA in cells activated in normoxic that were of HIF-1α mRNA in ex vivo T cells in and T cells their in not Therefore, but not hypoxia, to HIF-1α mRNA expression up-regulation in T cells. of T cells with a of such as in and and protein kinase C activation Rev. Biochem. 1994; PubMed Scopus Google Scholar). these may be in HIF-1α mRNA we the of protein kinase C and It that these are in for the observed in HIF-1α mRNA expression. kinase C and were to the of on HIF-1α mRNA expression in T cells of HIF-1α mRNA up-regulation by of and protein kinase C such an not The HIF-1α mRNA up-regulation by in T cells to the mechanisms of HIF-1α up-regulation in studies The expression of HIF-1α mRNA of with the accumulation between and and of activation data both that HIF-1α mRNA is activation and that such induction of HIF-1α mRNA may the of HIF-1 in of immediate early genes in T cell The to and in mRNA expression is to be a of immediate early genes K. U. Curr. Opin. Immunol. 1995; PubMed Scopus Google Scholar). HIF-1α expression the of immediate early response we the HIF-1α mRNA expression in activated T cells in the of an of protein not affect up-regulation of HIF-1α mRNA in activated cells that in HIF-1α mRNA expression are accomplished by between HIF-1α mRNA the HIF-1α mRNA as the mechanisms observed in HIF-1α mRNA up-regulation in T we an HIF-1α mRNA suggesting that transcription of the HIF-1α HIF-1α mRNA is required for the of on HIF-1α mRNA expression in activated T cells. We that HIF-1α is an immediate early response gene in antigen receptor-activated T its transcription is T cell activation by we to the up-regulation of HIF-1α mRNA in T cells is to up-regulation of HIF-1α I.1 I.2 mRNA both It was shown that the two for HIF-1α I.1 and I.2 R.H. A. P. P. Gassmann M. J. Biochem. 1997; PubMed Scopus Google Scholar). I.2 HIF-1α mRNA is expressed a the expression of I.1 HIF-1α mRNA and be in and R.H. A. P. Gassmann M. 1998; PubMed Google Scholar). both HIF-1α mRNA is expressed in T we on T cells and cells for I.1 and I.2 The I.2 HIF-1α mRNA isoform is expressed in both and activated T cells in both hypoxic and I.1 mRNA was by T cell The I.1 mRNA was not observed in T cells T cell of I.1 and I.2 HIF-1α mRNA isoforms in a for I.1 and I.2 HIF-1α by It is shown that the I.1 HIF-1α mRNA isoform is by T cell activation but not hypoxia the I.2 is expressed Therefore, the regulation of these two isoforms in T cells and the of the of up-regulation of I.1 HIF-1α mRNA in T cells were on in we demonstrated the I.1 HIF-1α mRNA vivo. This was accomplished with a of inflammation in vivo, the is on activation of T and cells G. 1997; Google Scholar). It is shown that of results in a as by up-regulation of of and in It is also shown that I.1 mRNA expression is in T cells were also in lymphocytes and not these data that T cell receptor the HIF-1α I.1 mRNA isoform and in vivo conditions. It was to studies by the expression patterns and of and HIF-1α isoforms on protein in ability to expression of these two proteins by the observed accumulation of I.1 HIF-1α mRNA that I.1 mRNA be A. G. Wenger R.H. Gassmann M. 2000; PubMed Scopus Google Scholar) the HIF-1α protein isoform 12 amino acid the as with the long I.2 isoform that amino acid G. S. Gene 1997; Google Scholar) We were to between these two protein isoforms of the between these proteins not This studies of HIF-1α isoforms on protein by were DNA the short HIF-1α isoform and long HIF-1α isoform similar I.1 isoform the amino of the basic that is in DNA and with but the that the of the 12 N-terminal amino affect the HIF-1 as a transcriptional short I.1 HIF-1α DNA binding activity similar to that of the I.2 we the binding of in HIF-1α isoforms to of in HIF-1α isoforms that of both isoforms is in with their for I.1 HIF-1α, for I.2 HIF-1α, and for data that both short and long HIF-1α isoforms display the ability to data results of A. A. G. Wenger R.H. Gassmann M. 2000; PubMed Scopus Google that the of 12 amino to the basic not HIF-1 DNA binding not these two isoforms display the transcriptional the ability of I.1 and I.2 HIF-1α isoforms to the HIF-1α and expression were to cells with the element the expression was by both and they similar transcriptional activity with HIF-1α Therefore, both short and long isoforms the ability to to and transcription of we the up-regulation of HIF-1α in activated T cells an effect on the transcription of genes in normoxic conditions. HIF-1α expression is by T cell activation may the transcription of its genes to be This was by of and two genes known as genes for HIF-1α J.A. Jiang B.-H. Iyer N.V. Agani F. Leung S.W. Semenza G.L. Mol. Cell. Biol. 1996; 16: PubMed Scopus Google Scholar, N.S. S. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, Y. Morita T. S. Res. 1995; PubMed Scopus Google Scholar, G. T. A. J. 1995; PubMed Scopus Google Scholar, Semenza G.L. M.H. Am. J. Physiol. 1998; Google Scholar). of cells demonstrated that transcription of and was enhanced in activated T cells A and of HIF-1 genes is enhanced in activated T for mRNA cells. were with and for The of the and are by is is The of mRNA cells is as were for mRNA expression. for mRNA cells. were activated as The of are the up-regulation of HIF-1α mRNA in antigen receptor-activated T differences in regulation of expression of I.1 and I.2 isoforms of HIF-1α and protein up-regulation of I.1 HIF-1α HIF-1α as an immediate early response and similar transcriptional activity for both long and short HIF-1α protein suggesting that they may be to the of genes but different physiological I.1 HIF-1α mRNA is not expressed in a R.H. A. P. Gassmann M. 1998; PubMed Google but is also expressed in a cell This may an for the in HIF-1α mRNA in M. Yu A.Y. Semenza G.L. J. 1999; PubMed Scopus Google Scholar, Booth G. Semenza G.L. Biochem. Res. 1996; PubMed Scopus Google Scholar, A.Y. Wiener K. Semenza G.L. Am. J. Physiol. 1998; PubMed Google Scholar) as cell activation during adaptation of to hypoxia to HIF-1α mRNA expression the between that the hypoxia-independent HIF-1α mRNA expression in R.H. A. Gassmann M. Marti H.H. Kidney Int. 1997; 51: Full Text PDF PubMed Scopus Google Scholar, R.H. A. Marti H.H. Gassmann M. Biochem. Res. 1996; PubMed Scopus Google Scholar) and of HIF-1α mRNA up-regulation in vivo in in hypoxic M. Yu A.Y. Semenza G.L. J. 1999; PubMed Scopus Google Scholar, Booth G. Semenza G.L. Biochem. Res. 1996; PubMed Scopus Google Scholar, A.Y. Wiener K. Semenza G.L. Am. J. Physiol. 1998; PubMed Google Scholar). the in regulation of HIF-1α mRNA by hypoxia in vivo and in be explained by different mechanisms of oxygen is to be The up-regulation of short HIF-1α isoform in in vivo activated T cells during the of the physiological of these The the of HIF-1α in T cell not to hypoxia, were not the of hypoxia-inducible may the and role of HIF-1α in both and of T cells. was shown that T cells and lymphocytes C. S. K. M. Cancer Res. 1995; Google the role of T cells in The in as to T cells activation to selective transcription of I.1 HIF-1α It is also to activated T cells an HIF-1α gene of of HIF-1α as was in cells in hypoxic conditions. HIF-1α exist in two be the acid in the of the HIF-1 protein may in in its interactions for cell proteins such as p53 and affect cell proliferation (23An W.G. Kanekal M. Simon M.C. Maltepe E. Blagosklonny M.V. Neckers L.M. Nature. 1998; 392: 405-408Crossref PubMed Scopus (660) Google Scholar, P. Y. D. K. M. M. F. R. P. P. D. E. Nature. 1998; PubMed Scopus Google Scholar). This of short HIF-1α be for the T cell activation is the short HIF-1α a different the long isoform to interact with other the differences between two HIF-1α isoforms I.1 and I.2 are to be studies the differences in DNA and transcriptional between these two HIF-1α isoforms and in activated T cells is by short long HIF-1α The selective up-regulation of I.1 HIF-1α isoform in activated T cells is explained by differences in of these two isoforms The I.2 is the R.H. A. P. Gassmann M. 1998; PubMed Google is with the of genes Curr. Opin. Dev. 1995; PubMed Scopus Google the of I.1 R.H. A. P. Gassmann M. 1998; PubMed Google Scholar). the binding was shown to be an of gene expression in lymphocytes J. Biol. 1998; PubMed Scopus Google Scholar) is in the I.1 R.H. A. P. Gassmann M. 1998; PubMed Google Scholar). The of HIF-1α mRNA was E. E. G. J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google but in a It be to HIF-1α also of two mRNA on expression of these isoforms may on mechanisms of HIF-1α and of HIF-1 as transcription factor its on other proteins such as p53 (23An W.G. Kanekal M. Simon M.C. Maltepe E. Blagosklonny M.V. Neckers L.M. Nature. 1998; 392: 405-408Crossref PubMed Scopus (660) Google Scholar). The up-regulation of HIF-1α mRNA in antigen receptor-activated T cells was an This the that HIF-1α mRNA expression is oxygen HIF-1α protein is activity P. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. L.E. W.G. Cell Biol. 2000; PubMed Scopus Google Scholar) in conditions. This not be were not for the alternatively spliced HIF-1α mRNA by Wenger R.H. A. P. P. Gassmann M. J. Biochem. 1997; PubMed Scopus Google Scholar). This to I.1 I.2 HIF-1α mRNA isoform expression patterns The HIF-1α mRNA up-regulation be and as up-regulation of the short HIF-1α mRNA This the the I.1 isoform as was and expected and HIF-1α I.2 mRNA is expressed protein up-regulation of I.1 mRNA HIF-1α as an immediate early response gene K. U. Curr. Opin. Immunol. 1995; PubMed Scopus Google Scholar). This that HIF-1α is early activation of lymphocytes by the The ability to between these on the of differences between long and short isoforms of The and gene data that both isoforms similar transcriptional It to be these two isoforms similar different protein-protein The oxygen HIF-1α be expected to with both short and long HIF-1α both isoforms an both isoforms not to be normoxic the expression of HIF-1α in T cells may be by a in the ability of to the short HIF-1α for was shown that activation of receptor E. J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Google Scholar) results in HIF-1α likely by activity of K. Semenza G.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). This may to of HIF-1α by the of oxygen J. 20: PubMed Scopus Google Scholar). It be to in studies the is to affect the It is that both HIF-1α isoforms are to in normoxic conditions. The ability to expression of HIF-1α protein under normoxic in activated T cells with that HIF-1α is not in activated T cells that the of HIF-1α is the of its This may as the of The a role of HIF-1α in the regulation of lymphocyte activation and to the for studies of factor in activated lymphocytes as a to mechanisms of HIF-1α We are to R. Wenger and M. Gassmann for the of and G. Semenza and O. for of HIF-1α and J. for the of and M. Blagosklonny for M. for in and P. and S. for the in and in the
Lukashev et al. (Sat,) studied this question.