Novel Function of Orphan Nuclear Receptor Nur77 in Stabilizing Hypoxia-inducible Factor-1α

Hypoxia-inducible factor-1α (HIF-1α) plays a central role in oxygen homeostasis by inducing the expression of a broad range of genes in a hypoxia-dependent manner. Here, we show that the orphan nuclear receptor Nur77 is an important regulator of HIF-1α. Under hypoxic conditions, Nur77 protein and transcripts were induced in a time-dependent manner. When Nur77 was exogenously introduced, it enhanced the transcriptional activity of HIF-1, whereas the dominant negative Nur77 mutant abolished the function of HIF-1. The HIF-1α protein was greatly increased and completely localized in the nucleus when coexpressed with Nur77. The N-terminal transactivation domain of Nur77 was required and sufficient for the activation of HIF-1α. The association of HIF-1α with von Hippel-Lindau protein was not affected, whereas that with mouse double minute 2 (MDM2) was greatly reduced in the presence of Nur77. Further we found that the expression of MDM2 was repressed at transcription level in the presence of Nur77 as well as under hypoxic conditions. Finally, PD98059 decreased Nur77-induced HIF-1α stability and recovered MDM2 expression, indicating that the extracellular signal-regulated kinase pathway is critical in the Nur77-induced activation of HIF-1α. Together, our results demonstrate a novel function for Nur77 in the stabilization of HIF-1α and suggest a potential role for Nur77 in tumor progression and metastasis. Hypoxia-inducible factor-1α (HIF-1α) plays a central role in oxygen homeostasis by inducing the expression of a broad range of genes in a hypoxia-dependent manner. Here, we show that the orphan nuclear receptor Nur77 is an important regulator of HIF-1α. Under hypoxic conditions, Nur77 protein and transcripts were induced in a time-dependent manner. When Nur77 was exogenously introduced, it enhanced the transcriptional activity of HIF-1, whereas the dominant negative Nur77 mutant abolished the function of HIF-1. The HIF-1α protein was greatly increased and completely localized in the nucleus when coexpressed with Nur77. The N-terminal transactivation domain of Nur77 was required and sufficient for the activation of HIF-1α. The association of HIF-1α with von Hippel-Lindau protein was not affected, whereas that with mouse double minute 2 (MDM2) was greatly reduced in the presence of Nur77. Further we found that the expression of MDM2 was repressed at transcription level in the presence of Nur77 as well as under hypoxic conditions. Finally, PD98059 decreased Nur77-induced HIF-1α stability and recovered MDM2 expression, indicating that the extracellular signal-regulated kinase pathway is critical in the Nur77-induced activation of HIF-1α. Together, our results demonstrate a novel function for Nur77 in the stabilization of HIF-1α and suggest a potential role for Nur77 in tumor progression and metastasis. Hypoxia-inducible factor-1 (HIF-1) 1The abbreviations used are: MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; VEGF, vascular endothelial growth factor; HRE, hypoxia response element; HIF-1, hypoxia-inducible factor-1; MDM2, mouse double minute 2; GFP, green fluorescent protein; β-gal, β-galactosidase; PMA, phorbol 12-myristate 13-acetate; VHL, von Hippel-Lindau; PHD, prolyl hydroxylase; NBRE, Nur77-binding response element; RT, reverse transcription; DN, dominant negative; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase. plays an essential role in cellular adaptation to changes in oxygen availability (reviewed in Ref. 1Semenza G.L. Trends. Mol. Med. 2001; 7: 345-350Abstract Full Text Full Text PDF PubMed Scopus (808) Google Scholar). Under hypoxic conditions, HIF-1 stimulates the transcription of diverse genes encoding proteins that function to increase oxygen delivery, to allow metabolic adaptation, and to promote cell survival. HIF-1 consists of α and β subunits, both of which belong to the basic helix-loop-helix PER-ARNTSIM (bHLH-PAS) protein family. Whereas HIF-1β, the previously described aryl hydrocarbon receptor nuclear translocator, is quite stable under normoxic conditions, HIF-1α is extremely unstable and is quickly degraded by the ubiquitin-proteasome system (2Huang L.E. Gu J. Schau M. Bunn H.F. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 7987-7992Crossref PubMed Scopus (1855) Google Scholar, 3Kallio P.J. Wilson W.J. O'Brien S. Makino Y. Poellinger L. J. Biol. Chem. 1999; 274: 6519-6525Abstract Full Text Full Text PDF PubMed Scopus (695) Google Scholar). The tumor suppressor von Hippel-Lindau (VHL) protein interacts with hydroxylated HIF-1α at proline residues in the presence of oxygen, leading to the proteolysis of HIF-1α (4Kamura T. Sato S. Iwai K. Czyzyk-Krzeska M. Conaway R.C. Conaway J.W. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 10430-10435Crossref PubMed Scopus (554) Google Scholar, 5Tanimoto K. Makino Y. Pereira T. Poellinger L. EMBO J. 2000; 19: 4298-4309Crossref PubMed Google Scholar). Specific prolyl hydroxylases (PHDs) catalyze the hydroxylation of the proline residue in the oxygen-dependent degradation domain of HIF-1α (6Berra E. Benizri E. Ginouves A. Volmat V. Roux D. Pouyssegur J. EMBO J. 2003; 22: 4082-4090Crossref PubMed Scopus (1101) Google Scholar, 7Cioffi C.L. Liu X.Q. Kosinski P.A. Garay M. Bowen B.R. Biochem. Biophys. Res. Commun. 2003; 303: 947-953Crossref PubMed Scopus (149) Google Scholar, 8Erez N. Milyavsky M. Eilam R. Shats I. Goldfinger N. Rotter V. Cancer Res. 2003; 63: 8777-8783PubMed Google Scholar). Three human PHDs, i.e. PHD1, -2, and -3, are expressed ubiquitously, although each isoform differs in the relative amount of transcripts expressed (7Cioffi C.L. Liu X.Q. Kosinski P.A. Garay M. Bowen B.R. Biochem. Biophys. Res. Commun. 2003; 303: 947-953Crossref PubMed Scopus (149) Google Scholar). Further activation of HIF-1α involves its nuclear translocation, dimerization with HIF-1β, DNA binding, and the recruitment of its transcriptional coactivators, such as the cyclic AMP response element-binding protein (CBP)/p300 (9Ema M. Hirota K. Mimura J. Abe H. Yodoi J. Sogawa K. Poellinger L. Fujii-Kuriyama Y. EMBO J. 1999; 18: 1905-1914Crossref PubMed Google Scholar). The cooperative binding of VHL and the factor-inhibiting HIF-1, which recruits histone deacetylases to HIF-1α under normoxic conditions, represses the transactivation function of HIF-1α (10Mahon P.C. Hirota K. Semenza G.L. Genes Dev. 2001; 15: 2675-2686Crossref PubMed Scopus (1139) Google Scholar). Indeed, the factor inhibiting HIF-1 was identified as an asparaginyl hydroxylase enzyme that modifies asparagine 803 of HIF-1α using an oxygen molecule, which results in the dissociation of HIF-1α and its coactivator p300 (11Lando D. Peet D.J. Gorman J.J. Whelan D.A. Whitelaw M.L. Bruick R.K. Genes Dev. 2002; 16: 1466-1471Crossref PubMed Scopus (1234) Google Scholar). These processes are regulated by post-translational modifications, in that the phosphorylation of HIF-1α via the Ras/Raf/MEK/p42/p44 signaling pathway leads to an enhanced transactivation function of HIF-1α (12Richard D.E. Berra E. Gothie E. Roux D. Pouyssegur J. J. Biol. Chem. 1999; 274: 32631-32637Abstract Full Text Full Text PDF PubMed Scopus (719) Google Scholar, 13Hur E. Chang K.Y. Lee E. Lee S.K. Park H. Mol. Pharmacol. 2001; 59: 1216-1224Crossref PubMed Scopus (114) Google Scholar). Recently, acetylation of HIF-1α by ARD-1 was shown to enhance its interaction with VHL, resulting in the proteasomal degradation of HIF-1α (14Jeong J.W. Bae M.K. Ahn M.Y. Kim S.H. Sohn T.K. Bae M.H. Yoo M.A. Song E.J. Lee K.J. Kim K.W. Cell. 2002; 111: 709-720Abstract Full Text Full Text PDF PubMed Scopus (606) Google Scholar). Although hypoxia is a strong and universal stimulus that activates HIF-1, a significant number of other hormonal, environmental, and intracellular stimuli have been reported to induce HIF-1 activation, probably in a cell-type-specific manner (15Zelzer E. Levy Y. Kahana C. Shilo B.Z. Rubinstein M. Cohen B. EMBO J. 1998; 17: 5085-5094Crossref PubMed Scopus (498) Google Scholar, 16Richard D.E. Berra E. Pouyssegur J. J. Biol. Chem. 2000; 275: 26765-26771Abstract Full Text Full Text PDF PubMed Google Scholar, 17Chan D.A. Sutphin P.D. Denko N.C. Giaccia A.J. J. Biol. Chem. 2002; 277: 40112-40117Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar). One of these factors, p53, a key regulator of the response to cellular stress, directly interacts with HIF-1α and decreases the level of HIF-1α protein by promoting mouse double minute 2 (MDM2)-mediated ubiquitination and the subsequent proteasomal degradation of HIF-1α (18Ravi R. Mookerjee B. Bhujwalla Z.M. Sutter C.H. Artemov D. Zeng Q. Dillehay L.E. Madan A. Semenza G.L. Bedi A. Genes Dev. 2000; 14: 34-44Crossref PubMed Google Scholar). In contrast, oncogenic proteins such as v-Src and RasV12 result in the loss of hydroxylated proline 564 and thereby stabilize HIF-1α (17Chan D.A. Sutphin P.D. Denko N.C. Giaccia A.J. J. Biol. Chem. 2002; 277: 40112-40117Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar). We have recently shown that hepatitis B virus X protein, a major viral transactivator of hepatitis B virus, increases the transcriptional activity of HIF-1α by stabilizing the protein via the extracellular signal-regulated kinase (ERK) signaling pathway (19Yoo Y.G. Oh S.H. Park H. Lee N. Park H. Kim Lee J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). the stability of HIF-1α is by a of intracellular which as hypoxia and other Nur77 as and is an orphan of the receptor of transcriptional that is of an N-terminal transactivation a and a domain A. PubMed Scopus Google Scholar). Nur77 as a to the Nur77-binding response which the a of the and residues J. Mol. Cell. Biol. PubMed Scopus Google Scholar). Nur77 DNA as a as a with the X receptor T. L. Genes Dev. PubMed Scopus Google Scholar, A. S. R. M.H. Y. J. Mol. Cell. Biol. 17: PubMed Scopus Google Scholar). Nur77 is when that the orphan receptor not of have a role for Nur77 in cellular and major cellular Nur77 expression is induced by growth and D. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, Mol. Cell. Biol. PubMed Scopus Google Scholar, Mol. Cell. Biol. 14: PubMed Scopus Google Scholar). growth factor and induce Nur77 expression, which S.K. N. B. Mol. 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Nur77 is in both cellular and Nur77 is in the and progression of which are to result a in the these In the we a novel function of Nur77 in the transcriptional activity of HIF-1α and suggest a potential role for Nur77 in tumor progression and metastasis. and cell and human cell human cell human cell and mouse cell were the The were in essential at in an of with and The were to hypoxia by the in an in and at was induced by the with When the were to the was and were in a and for and cell were by subsequent of protein cell were to and to a was in in and with VEGF, VHL, MDM2, as described previously (19Yoo Y.G. Oh S.H. Park H. Lee N. Park H. Kim Lee J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). Nur77 protein, of cell were with of and with mouse H. Park Kim Biochem. Biophys. Res. Commun. 2001; PubMed Scopus Google Scholar). with were and proteins were using the The protein was by and Nur77 to and and the expression for Nur77 and dominant negative and MDM2 were described previously (19Yoo Y.G. Oh S.H. Park H. Lee N. Park H. Kim Lee J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, H. Park Kim Biochem. Biophys. Res. Commun. 2001; PubMed Scopus Google Scholar, A. Y. C.H. J.J. Y. E. EMBO J. 2002; PubMed Scopus Google Scholar). The of and were by the of The green fluorescent protein HIF-1α and the fluorescent Nur77 were by and of the was by expression of protein, in a in a in a were and The were with of expression using as described previously (19Yoo Y.G. Oh S.H. Park H. Lee N. Park H. Kim Lee J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). were in and The were with expression in the presence of Nur77 expression using the of activity was using an activity was for using the of was using of was and was using was as described previously (19Yoo Y.G. Oh S.H. Park H. Lee N. Park H. Kim Lee J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, H. Park Kim Biochem. Biophys. Res. Commun. 2001; PubMed Scopus Google with for Nur77 HIF-1α MDM2 and Genes were under the used to the was with for Nur77 and to of was to the were in a to the The was for of for and for the of each was and used for Nur77 expression were to and the relative level was using the as described previously K.J. 2001; PubMed Scopus Google Scholar). that been the a were with of each of using were with for the of the were with for and the were by was used to of Nur77 under the that Nur77 is in the hypoxic signaling we the of Nur77 expression under shown in when were under hypoxic conditions, the expression of Nur77 protein was The of Nur77 was as as and it for When the were with a a of was The level of Nur77 under hypoxia was as as that induced by phorbol 12-myristate and well of Nur77 A. S. L. A. Mol. Cell. Biol. 15: PubMed Scopus Google Scholar). The of Nur77 was by an increase in HIF-1α. and induced the expression of HIF-1α protein, which recently that stabilization of HIF-1α Lee E. Bae E.J. L.E. Kim Park J.W. Cancer Res. 2003; 63: Google Scholar). the increased Nur77 protein was we using a encoding NBRE, a Nur77-binding response H. Park Kim Biochem. Biophys. Res. Commun. 2001; PubMed Scopus Google Scholar). with the at the protein the was in the presence of at a level that in the presence of and The activity was enhanced when HIF-1α was indicating that HIF-1α have a role in the of Nur77 under hypoxia we the increase in Nur77 was at the level of The Nur77 transcripts increased and were at These results were when Nur77 was by the activity of the encoding the Nur77 was enhanced in the presence of and it was increased by with HIF-1α These results demonstrate that the expression of Nur77 is induced under hypoxia at the level of Nur77 the as as the of we the and of Nur77 in response to hypoxic We Nur77 and HIF-1, HIF-1α is a major regulator of expression in response to we Nur77 increases HIF-1 activity using with of the Nur77 expression and a hypoxia response that in the (9Ema M. Hirota K. Mimura J. Abe H. Yodoi J. Sogawa K. Poellinger L. Fujii-Kuriyama Y. EMBO J. 1999; 18: 1905-1914Crossref PubMed Google Scholar). shown in of the Nur77 expression activity in a whereas the expression of activity was enhanced when were with and activity was when both Nur77 and HIF-1α were These results that Nur77 the transcriptional activity of HIF-1 under hypoxic and in the of hypoxic the transcriptional activation of the protein is required to the nucleus P.J. K. O'Brien S. Makino Y. H. Poellinger L. EMBO J. 1998; 17: PubMed Google Scholar). the of HIF-1α was with using HIF-1α. was localized in both the nucleus and in the of whereas it was in the nucleus in the presence of the level of was enhanced and in the nucleus when Nur77 was These results demonstrate that Nur77 increases protein level as well as the nuclear of HIF-1α. Nur77 the of Nur77 increases the stability of we Nur77 and the level of HIF-1α of as well as that of vascular endothelial growth factor was increased with the expression of Nur77 and was increased in the presence of Although was greatly HIF-1α in the presence of Nur77 these results that Nur77 increases the level of HIF-1α protein the stabilization of we HIF-1α protein in the presence of which protein shown in Nur77 induced strong expression of HIF-1α and the degradation of HIF-1α as as The of HIF-1α protein was degraded under the of HIF-1α was in the presence of Nur77 to N-terminal of Nur77 to is of an N-terminal transactivation a and a domain We Nur77 to the domain that the stability of HIF-1α. the N-terminal transactivation domain activity in stabilizing whereas the stabilizing activity the dominant negative function A. PubMed Scopus Google Scholar, B. V. A. PubMed Scopus Google we the of the the stabilization and transactivation of HIF-1α. shown in repressed HIF-1α stabilization as well as the expression of that is induced by These results are with the results of the shown in The function of the N-terminal transactivation domain that induced the activation of HIF-1 was by the using the Nur77 the of MDM2, thereby the HIF-1α and we the by which Nur77 the stabilization of HIF-1α We Nur77 the association HIF-1α and VHL, which the proteasomal degradation of HIF-1α. shown in when were with the binding of HIF-1α and VHL was indicating that the binding of VHL to HIF-1α degradation of HIF-1α under as described previously (4Kamura T. Sato S. Iwai K. Czyzyk-Krzeska M. Conaway R.C. Conaway J.W. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 10430-10435Crossref PubMed Scopus (554) Google Scholar, 5Tanimoto K. Makino Y. Pereira T. Poellinger L. EMBO J. 2000; 19: 4298-4309Crossref PubMed Google Scholar). binding was in the presence of although binding was not when Nur77 was result that VHL is in the stabilization of it not with the Nur77-induced stability of HIF-1α. the degradation of HIF-1α is regulated by MDM2, we Nur77 the binding of HIF-1α to MDM2 to HIF-1α in the presence of binding was completely abolished in the presence of Nur77 In the presence of the expression of MDM2 protein was that the loss of MDM2 protein the in association of HIF-1α and We the of MDM2 expression by Nur77. When Nur77 was expressed in MDM2 expression was completely results were with other cell such as and The increase in HIF-1α stability in the presence of Nur77 was when MDM2 was exogenously was the N-terminal transactivation domain of Nur77 in stabilizing HIF-1α the expression of MDM2 was repressed by the N-terminal transactivation The result was to that with the mutant When we the level of MDM2 it was in the presence of indicating that the of MDM2 is at transcription level Together, these results show that MDM2 is by which to stabilization of HIF-1α. of MDM2 under that MDM2 under Nur77 is induced under these conditions. was in and and we found that MDM2 expression was reduced as The in MDM2 was by increases in the of Nur77 and HIF-1α proteins When the of the in MDM2 was it the increases in Nur77 and HIF-1α when the dominant negative was of MDM2 were of MDM2 under hypoxia was at transcription the level of MDM2 was decreased under hypoxic Together, our results demonstrate that the Nur77-induced of MDM2 is an important by which Nur77 the stabilization of HIF-1α. Nur77 of of the stability of HIF-1α was regulated by the signaling pathway R. Hirota K. Semenza G.L. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google we the of signaling pathway in the Nur77-induced stabilization of HIF-1α. When Nur77 was the was whereas PD98059 of abolished the phosphorylation as well as the of HIF-1α protein the in MDM2 expression by Nur77 was in the presence of The N-terminal transactivation domain of Nur77 induced phosphorylation of as as the Nur77 that the N-terminal domain of Nur77 is required and sufficient to induce the signaling pathway Together, these results demonstrate that pathway plays a critical role in the Nur77-induced activation of HIF-1α and that in MDM2 expression is an important that stabilization of HIF-1α. a in oxygen and results in the of by inducing the expression of the activation of a key transcriptional regulator of hypoxic (reviewed in 1Semenza G.L. Trends. Mol. Med. 2001; 7: 345-350Abstract Full Text Full Text PDF PubMed Scopus (808) Google and M. P.J. J. Natl. 2001; PubMed Scopus Google Scholar). been to the that the activity of HIF-1α to of tumor progression and to the of In we have shown that an orphan nuclear is induced under hypoxia and that it a role in stabilizing HIF-1α. We have identified the Nur77 and the tumor suppressor MDM2 by that Nur77 the expression of MDM2, which decreases degradation of HIF-1α. Under normoxic conditions, HIF-1α is degraded by the proteasomal and the ubiquitination of HIF-1α is by its interaction with VHL (4Kamura T. Sato S. Iwai K. Czyzyk-Krzeska M. Conaway R.C. Conaway J.W. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 10430-10435Crossref PubMed Scopus (554) Google Scholar, 5Tanimoto K. Makino Y. Pereira T. Poellinger L. EMBO J. 2000; 19: 4298-4309Crossref PubMed Google Scholar). In contrast, when Nur77 HIF-1α under normoxic conditions, the binding of HIF-1α to VHL is the expression of MDM2 and its subsequent binding to HIF-1α is indicating that the of MDM2 expression is the the Nur77-induced stabilization of HIF-1α with these when the expression of Nur77 is induced under the expression of MDM2 is in MDM2 protein under hypoxia been by R. C. R.K. Giaccia A.J. Cancer Res. 1999; 59: Google Scholar, Y. Y. D.A. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). exogenously the expression of MDM2 decreased the expression of HIF-1α result that MDM2 is an important regulator of HIF-1α stability and a major of Nur77 Although the by which Nur77 the expression of MDM2 is transcriptional of the MDM2 by Nur77 is DNA binding of Nur77 is not required in Recently, M. Mol. Cell. Biol. PubMed Scopus Google reported a that the expression of MDM2 to increased expression of HIF-1α and not the of HIF-1α. when MDM2 was in our of HIF-1α protein decreased not The for are not at The tumor p53, is a well transcriptional of MDM2, and MDM2 transcriptional activity by inducing the degradation of D. 2002; PubMed Scopus Google Scholar). Under hypoxic conditions, the stability of HIF-1α by promoting the ubiquitination and proteasomal degradation of HIF-1α (18Ravi R. Mookerjee B. Bhujwalla Z.M. Sutter C.H. Artemov D. Zeng Q. Dillehay L.E. Madan A. Semenza G.L. Bedi A. Genes Dev. 2000; 14: 34-44Crossref PubMed Google Scholar). of the expression of under hypoxic in are which the result of conditions, such as the of hypoxic stress, the of the cell and the cell used in C. A. D.E. Mol. Cell. Biol. 1998; 18: PubMed Scopus Google Scholar, Denko N.C. Giaccia A.J. Mol. Cell. 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In we that Nur77 induced activation of the which result in stabilization of HIF-1α that Nur77 and pathway to an intracellular signaling that HIF-1α the of Nur77 the activity at the that the N-terminal transactivation domain of Nur77 is sufficient to HIF-1α that the DNA binding the transcriptional function of Nur77 is required for the activation of HIF-1α. that Nur77 transactivation in the nucleus is with cell whereas P.J. Wilson W.J. O'Brien S. Makino Y. Poellinger L. J. Biol. Chem. 1999; 274: 6519-6525Abstract Full Text Full Text PDF PubMed Scopus (695) Google Scholar, S.K. N. B. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar, B. S.K. Liu Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). 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HIF-1α is at in human in and the expression of HIF-1α in been with tumor and (reviewed in 1Semenza G.L. Trends. Mol. Med. 2001; 7: 345-350Abstract Full Text Full Text PDF PubMed Scopus (808) Google and M. P.J. J. Natl. 2001; PubMed Scopus Google Scholar). In the we have shown that the expression of Nur77 is induced under hypoxic conditions, and and HIF-1α. Recently, it was reported that HIF-1α and Nur77 in cell J.W. Park Liu Cancer Res. PubMed Scopus Google Scholar). In an been shown to induce the expression of the Nur77 genes D. H. A. I. Biol. 2003; PubMed Scopus Google Scholar). These with our suggest a of HIF-1α and Nur77. results suggest that Nur77 a tumor in the of hypoxic stress, the activation of HIF-1α. of the in the stabilization of HIF-1α important with level expression of HIF-1α are and Nur77 a novel for the of that tumor progression and metastasis. We for the MDM2 expression