activating transcription factor 4


Summary: An activating transcription factor that regulates the expression of a variety of GENES involved in amino acid metabolism and transport. It also interacts with HTLV-I transactivator protein.

Top Publications

  1. Chen Y, Su J, Tsao C, Hung C, Chao H, Lin J, et al. Sinulariolide induced hepatocellular carcinoma apoptosis through activation of mitochondrial-related apoptotic and PERK/eIF2?/ATF4/CHOP pathway. Molecules. 2013;18:10146-61 pubmed publisher
    ..The current study suggested sinulariolide-induced hepatoma cell cytotoxicity involved multiple apoptotic signal pathways. This may implicate that sinulariolide is a potential compound for the treatment of hepatocellular carcinoma. ..
  2. Schaap F, Kremer A, Lamers W, Jansen P, Gaemers I. Fibroblast growth factor 21 is induced by endoplasmic reticulum stress. Biochimie. 2013;95:692-9 pubmed publisher
    ..Our findings suggest that increased cellular stress in fatty livers may underlie the elevated FGF21 levels observed in patients with NAFLD. ..
  3. De Sousa Coelho A, Marrero P, Haro D. Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation. Biochem J. 2012;443:165-71 pubmed publisher
    ..of eIF2 (eukaryotic initiation factor 2), global protein synthesis reduction and increased ATF4 (activating transcription factor 4). ATF4 modulates a wide spectrum of genes involved in the adaptation to dietary stress...
  4. Cao H, Yu S, Yao Z, Galson D, Jiang Y, Zhang X, et al. Activating transcription factor 4 regulates osteoclast differentiation in mice. J Clin Invest. 2010;120:2755-66 pubmed publisher
    b>Activating transcription factor 4 (ATF4) is a critical transcription factor for osteoblast (OBL) function and bone formation; however, a direct role in osteoclasts (OCLs) has not been established...
  5. Luo J, Zhou W, Zhou X, Li D, Weng J, Yi Z, et al. Regulation of bone formation and remodeling by G-protein-coupled receptor 48. Development. 2009;136:2747-56 pubmed publisher
    ..Together, our data demonstrate that Gpr48 regulates bone formation and remodeling through the cAMP-PKA-Atf4 signaling pathway. ..
  6. Gjymishka A, Palii S, Shan J, Kilberg M. Despite increased ATF4 binding at the C/EBP-ATF composite site following activation of the unfolded protein response, system A transporter 2 (SNAT2) transcription activity is repressed in HepG2 cells. J Biol Chem. 2008;283:27736-47 pubmed publisher
    ..suppresses global protein synthesis but enhances translation of selected mRNAs such as that for activating transcription factor 4 (ATF4)...
  7. Yoshizawa T, Hinoi E, Jung D, Kajimura D, Ferron M, Seo J, et al. The transcription factor ATF4 regulates glucose metabolism in mice through its expression in osteoblasts. J Clin Invest. 2009;119:2807-17 pubmed publisher
    ..b>Activating transcription factor 4 (ATF4) is a transcription factor that accumulates predominantly in osteoblasts, where it regulates ..
  8. Krokowski D, Han J, Saikia M, Majumder M, Yuan C, Guan B, et al. A self-defeating anabolic program leads to ?-cell apoptosis in endoplasmic reticulum stress-induced diabetes via regulation of amino acid flux. J Biol Chem. 2013;288:17202-13 pubmed publisher
    ..These studies suggest that the increased expression of amino acid transporters in islets can serve as early diagnostic biomarkers for the development of diabetes. ..
  9. Lian N, Lin T, Liu W, Wang W, Li L, Sun S, et al. Transforming growth factor ? suppresses osteoblast differentiation via the vimentin activating transcription factor 4 (ATF4) axis. J Biol Chem. 2012;287:35975-84 pubmed publisher
    ..Thus, our study identifies that TGF? stimulates vimentin production via PI3K-Akt-mTOR signaling, which leads to suppression of ATF4-dependent Ocn transcription and osteoblast differentiation. ..

More Information


  1. Zong Z, Du Z, Li N, Li C, Zhang Q, Liu B, et al. Implication of Nrf2 and ATF4 in differential induction of CHOP by proteasome inhibition in thyroid cancer cells. Biochim Biophys Acta. 2012;1823:1395-404 pubmed publisher
    ..We also demonstrated that although proteasome inhibition caused similar accumulation of activating transcription factor 4 (ATF4) in a panel of thyroid cancer cells, distinct amounts of ATF4 were recruited to the AARE1 ..
  2. Valenzuela V, Collyer E, Armentano D, Parsons G, Court F, Hetz C. Activation of the unfolded protein response enhances motor recovery after spinal cord injury. Cell Death Dis. 2012;3:e272 pubmed publisher
    ..Ablation of X-box-binding protein 1 (XBP1) or activating transcription factor 4 (ATF4) expression, two major UPR transcription factors, leads to a reduced locomotor recovery after ..
  3. Carraro V, Maurin A, Lambert Langlais S, Averous J, Chaveroux C, Parry L, et al. Amino acid availability controls TRB3 transcription in liver through the GCN2/eIF2?/ATF4 pathway. PLoS ONE. 2010;5:e15716 pubmed publisher
    ..Therefore, this work establishes for the first time that the molecular mechanisms involved in the regulation of gene transcription by amino acid availability are functional in mouse liver. ..
  4. Magne L, Blanc E, Legrand B, Lucas D, Barouki R, Rouach H, et al. ATF4 and the integrated stress response are induced by ethanol and cytochrome P450 2E1 in human hepatocytes. J Hepatol. 2011;54:729-37 pubmed publisher
  5. Shang Y, Zhong M, Zhang L, Guo Z, Wang Z, Zhang Y, et al. Tribble 3, a novel oxidized low-density lipoprotein-inducible gene, is induced via the activating transcription factor 4-C/EBP homologous protein pathway. Clin Exp Pharmacol Physiol. 2010;37:51-5 pubmed publisher
    ..The expression of CHOP and activating transcription factor 4 (ATF4) mRNA in treated cells was detected by quantitative real-time polymerase chain reaction (PCR)...
  6. Karsenty G. Transcriptional control of skeletogenesis. Annu Rev Genomics Hum Genet. 2008;9:183-96 pubmed publisher
  7. Korfei M, Ruppert C, Mahavadi P, Henneke I, Markart P, Koch M, et al. Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2008;178:838-46 pubmed publisher
    ..Severe ER stress response in the AECIIs of patients with sporadic IPF may underlie the apoptosis of this cell type and development of fibrosis in this disease. ..
  8. Jousse C, Deval C, Maurin A, Parry L, Cherasse Y, Chaveroux C, et al. TRB3 inhibits the transcriptional activation of stress-regulated genes by a negative feedback on the ATF4 pathway. J Biol Chem. 2007;282:15851-61 pubmed defined as a highly conserved response to several stresses that converge to the induction of the activating transcription factor 4 (ATF4)...
  9. Caselli E, Benedetti S, Grigolato J, Caruso A, Di Luca D. Activating transcription factor 4 (ATF4) is upregulated by human herpesvirus 8 infection, increases virus replication and promotes proangiogenic properties. Arch Virol. 2012;157:63-74 pubmed publisher
    ..We analysed activating transcription factor 4 (ATF4), since it is central in the cellular response to stress and is involved in angiogenesis...
  10. Dey S, Baird T, Zhou D, Palam L, Spandau D, Wek R. Both transcriptional regulation and translational control of ATF4 are central to the integrated stress response. J Biol Chem. 2010;285:33165-74 pubmed publisher
  11. Kilberg M, Shan J, Su N. ATF4-dependent transcription mediates signaling of amino acid limitation. Trends Endocrinol Metab. 2009;20:436-43 pubmed publisher
    ..Therefore, understanding the transcriptional programs initiated by amino acid limitation is crucial and timely. ..
  12. Cherasse Y, Maurin A, Chaveroux C, Jousse C, Carraro V, Parry L, et al. The p300/CBP-associated factor (PCAF) is a cofactor of ATF4 for amino acid-regulated transcription of CHOP. Nucleic Acids Res. 2007;35:5954-65 pubmed
    ..a signaling cascade is triggered that leads to increased translation of the 'master regulator', activating transcription factor 4 (ATF4), and resulting in the induction of specific target genes...
  13. Hengstermann A, Muller T. Endoplasmic reticulum stress induced by aqueous extracts of cigarette smoke in 3T3 cells activates the unfolded-protein-response-dependent PERK pathway of cell survival. Free Radic Biol Med. 2008;44:1097-107 pubmed publisher
    ..Since ER stress has been linked to diseases that are also related to CS exposure, these data are relevant in the discussion of a general molecular mechanism of CS-induced disease. ..
  14. Ye J, Koumenis C. ATF4, an ER stress and hypoxia-inducible transcription factor and its potential role in hypoxia tolerance and tumorigenesis. Curr Mol Med. 2009;9:411-6 pubmed
    ..Here we summarize recent findings regarding the regulation of ATF4 in transformed cells, clinical tumor samples and tumor models, and speculate on its potential role in tumor progression and chemoresistance. ..
  15. Gardner L. Hypoxic inhibition of nonsense-mediated RNA decay regulates gene expression and the integrated stress response. Mol Cell Biol. 2008;28:3729-41 pubmed publisher
    ..Our demonstration that NMD is inhibited in hypoxic cells reveals that the regulation of NMD can dynamically alter gene expression and also establishes a novel mechanism for hypoxic gene regulation. ..
  16. Duan X, Chang J, Zhang J, Zhang B, Li Y, Teng X, et al. Activating transcription factor 4 is involved in endoplasmic reticulum stress-mediated apoptosis contributing to vascular calcification. Apoptosis. 2013;18:1132-44 pubmed publisher
    ..b>Activating transcription factor 4 (ATF4) is a critical transcription factor in osteoblastogenesis and ERS-induced apoptosis...
  17. Cho H, Wu M, Zhang L, Thompson R, Nath A, Chan C. Signaling dynamics of palmitate-induced ER stress responses mediated by ATF4 in HepG2 cells. BMC Syst Biol. 2013;7:9 pubmed publisher
    ..The in silico model helped to delineate the essential signaling pathways in palmitate-mediated apoptosis. ..
  18. Sequeira S, Ranganathan A, Adam A, Iglesias B, Farias E, Aguirre Ghiso J. Inhibition of proliferation by PERK regulates mammary acinar morphogenesis and tumor formation. PLoS ONE. 2007;2:e615 pubmed
    ..The possibility that deficiencies in PERK signaling could lead to hyperproliferation of the mammary epithelium and increase the likelihood of tumor formation, is of significance to the understanding of breast cancer. ..
  19. Frank C, Ge X, Xie Z, Zhou Y, Tsai L. Control of activating transcription factor 4 (ATF4) persistence by multisite phosphorylation impacts cell cycle progression and neurogenesis. J Biol Chem. 2010;285:33324-37 pubmed publisher
    ..We propose that precise regulation of the ATF4 dosage impacts cell cycle control and impinges on neurogenesis. ..
  20. Lee E, Yoon C, Kim Y, Bae Y. The double-strand RNA-dependent protein kinase PKR plays a significant role in a sustained ER stress-induced apoptosis. FEBS Lett. 2007;581:4325-32 pubmed
    ..These results indicate that the ER-stress-mediated eIF2alpha/ATF4/CHOP/cell death pathway is, to some degree, dependent on PACT-mediated PKR activation apart from the PERK pathway. ..
  21. Tominaga H, Maeda S, Hayashi M, Takeda S, Akira S, Komiya S, et al. CCAAT/enhancer-binding protein beta promotes osteoblast differentiation by enhancing Runx2 activity with ATF4. Mol Biol Cell. 2008;19:5373-86 pubmed publisher
    ..reporter, gel shift, DNAP, and ChIP assays demonstrated that C/EBPbeta heterodimerized with activating transcription factor 4 (ATF4), another basic leucine zipper transcription factor crucial for osteoblast maturation...
  22. Rzymski T, Paantjens A, Bod J, Harris A. Multiple pathways are involved in the anoxia response of SKIP3 including HuR-regulated RNA stability, NF-kappaB and ATF4. Oncogene. 2008;27:4532-43 pubmed publisher
    ..b>Activating transcription factor 4 (ATF4) is a mediator of the UPR and activates a gene expression program, promoting tumour growth and ..
  23. Marchand A, Tomkiewicz C, Magne L, Barouki R, Garlatti M. Endoplasmic reticulum stress induction of insulin-like growth factor-binding protein-1 involves ATF4. J Biol Chem. 2006;281:19124-33 pubmed
    ..A distal regulatory region of the human IGFBP-1 gene (-6682/-6384) containing an activating transcription factor 4 (ATF4) composite site was required for promoter activation upon ER stress...
  24. van den Beucken T, Koritzinsky M, Niessen H, Dubois L, Savelkouls K, Mujcic H, et al. Hypoxia-induced expression of carbonic anhydrase 9 is dependent on the unfolded protein response. J Biol Chem. 2009;284:24204-12 pubmed publisher
    ..Our data indicate that expression of CA9 is regulated through both the HIF-1 and unfolded protein response hypoxia response pathways in vitro and in vivo. ..
  25. Malabanan K, Kanellakis P, Bobik A, Khachigian L. Activation transcription factor-4 induced by fibroblast growth factor-2 regulates vascular endothelial growth factor-A transcription in vascular smooth muscle cells and mediates intimal thickening in rat arteries following balloon injury. Circ Res. 2008;103:378-87 pubmed publisher
    ..These findings reveal, for the first time, the induction of ATF-4 by both vascular injury and FGF-2. ATF-4 serves as a conduit for the inducible expression of 1 growth factor by another during the process of intimal thickening. ..
  26. Jin H, Seo S, Woo S, Kim E, Lee H, Yoo D, et al. Activating transcription factor 4 and CCAAT/enhancer-binding protein-beta negatively regulate the mammalian target of rapamycin via Redd1 expression in response to oxidative and endoplasmic reticulum stress. Free Radic Biol Med. 2009;46:1158-67 pubmed publisher
    ..In this study, we show that activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein-beta (C/EBP-beta) negatively regulate mTOR via Redd1 ..
  27. Miyamoto N, Izumi H, Miyamoto R, Bin H, Kondo H, Tawara A, et al. Transcriptional regulation of activating transcription factor 4 under oxidative stress in retinal pigment epithelial ARPE-19/HPV-16 cells. Invest Ophthalmol Vis Sci. 2011;52:1226-34 pubmed publisher
    ..b>Activating transcription factor 4 (ATF4) is induced by various stressors, including endoplasmic reticulum (ER) and oxidative stress, ..
  28. Xu L, Su L, Liu X. PKC? regulates death receptor 5 expression induced by PS-341 through ATF4-ATF3/CHOP axis in human lung cancer cells. Mol Cancer Ther. 2012;11:2174-82 pubmed publisher
    ..Collectively, we show that PS-341 induces PKC?-dependent DR5 expression through activation of ERK/RSK2 and ER stress signaling pathway. ..
  29. Su N, Kilberg M. C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene. J Biol Chem. 2008;283:35106-17 pubmed publisher
    ..Collectively, the results document that CHOP is a member of the transcription factor network that controls the stress-induced regulation of specific C/EBP-ATF-containing genes, such as ASNS. ..
  30. Costa Mattioli M, Gobert D, Stern E, Gamache K, Colina R, Cuello C, et al. eIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory. Cell. 2007;129:195-206 pubmed
    ..These findings highlight the importance of a single phosphorylation site in eIF2alpha as a key regulator of L-LTP and LTM formation. ..
  31. Palam L, Baird T, Wek R. Phosphorylation of eIF2 facilitates ribosomal bypass of an inhibitory upstream ORF to enhance CHOP translation. J Biol Chem. 2011;286:10939-49 pubmed publisher
    ..This new mechanism of translational control explains how expression of CHOP and the fate of cells are tightly linked to the levels of phosphorylated eIF2 and stress damage. ..
  32. Clavarino G, Cláudio N, Dalet A, Terawaki S, Couderc T, Chasson L, et al. Protein phosphatase 1 subunit Ppp1r15a/GADD34 regulates cytokine production in polyinosinic:polycytidylic acid-stimulated dendritic cells. Proc Natl Acad Sci U S A. 2012;109:3006-11 pubmed publisher
    ..GADD34, however, was shown to be required for normal cytokine production both in vitro and in vivo. These observations have important implications in linking further pathogen detection with the integrated stress response pathways. ..
  33. Caselli E, Benedetti S, Gentili V, Grigolato J, Di Luca D. Short communication: activating transcription factor 4 (ATF4) promotes HIV type 1 activation. AIDS Res Hum Retroviruses. 2012;28:907-12 pubmed publisher
    b>Activating transcription factor 4 (ATF4) is a central factor in the cellular response to multiple stresses, including altered metabolic conditions, anoxia and hypoxia, and redox stress...
  34. Teske B, Baird T, Wek R. Methods for analyzing eIF2 kinases and translational control in the unfolded protein response. Methods Enzymol. 2011;490:333-56 pubmed publisher
    ..Together, these experimental descriptions will provide a useful molecular "toolkit" to study each feature of the translational control processes invoked during ER stress. ..
  35. Elefteriou F, Benson M, Sowa H, Starbuck M, Liu X, Ron D, et al. ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metab. 2006;4:441-51 pubmed
    ..By showing that ATF4-dependent skeletal dysplasiae are treatable by dietary manipulations, this study reveals a molecular connection between nutrition and skeletal development...
  36. Ye J, Kumanova M, Hart L, Sloane K, Zhang H, De Panis D, et al. The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J. 2010;29:2082-96 pubmed publisher
    ..We conclude that the GCN2-eIF2alpha-ATF4 pathway is critical for maintaining metabolic homeostasis in tumour cells, making it a novel and attractive target for anti-tumour approaches. ..
  37. Gargalovic P, Gharavi N, Clark M, Pagnon J, Yang W, He A, et al. The unfolded protein response is an important regulator of inflammatory genes in endothelial cells. Arterioscler Thromb Vasc Biol. 2006;26:2490-6 pubmed
    ..These data suggest that the UPR pathway is a general mediator of vascular inflammation and EC dysfunction in atherosclerosis, and, likely, other inflammatory disorders. ..
  38. Zhang X, Yu S, Galson D, Luo M, Fan J, Zhang J, et al. Activating transcription factor 4 is critical for proliferation and survival in primary bone marrow stromal cells and calvarial osteoblasts. J Cell Biochem. 2008;105:885-95 pubmed publisher
    b>Activating transcription factor 4 (ATF4) is essential for bone formation. However, the mechanism of its actions in bone is poorly understood...
  39. Zhu H, Xia L, Zhang Y, Wang H, Xu W, Hu H, et al. Activating transcription factor 4 confers a multidrug resistance phenotype to gastric cancer cells through transactivation of SIRT1 expression. PLoS ONE. 2012;7:e31431 pubmed publisher
    Multidrug resistance (MDR) in gastric cancer remains a major challenge to clinical treatment. Activating transcription factor 4 (ATF4) is a stress response gene involved in homeostasis and cellular protection...
  40. Yusta B, Baggio L, Estall J, Koehler J, Holland D, Li H, et al. GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress. Cell Metab. 2006;4:391-406 pubmed
    ..These findings demonstrate that GLP-1R signaling directly modulates the ER stress response leading to promotion of beta cell adaptation and survival. ..
  41. Gombart A, Grewal J, Koeffler H. ATF4 differentially regulates transcriptional activation of myeloid-specific genes by C/EBPepsilon and C/EBPalpha. J Leukoc Biol. 2007;81:1535-47 pubmed
    ..The activating transcription factor 4 (ATF4) protein was identified as a principal partner for the myeloid-specific transcriptional factor ..
  42. Gupta S, Read D, Deepti A, Cawley K, Gupta A, Oommen D, et al. Perk-dependent repression of miR-106b-25 cluster is required for ER stress-induced apoptosis. Cell Death Dis. 2012;3:e333 pubmed publisher
    ..and Mcm-7 (host gene of miR-106b-25) is co-regulated through the transcription factors Atf4 (activating transcription factor 4) and Nrf2 (nuclear factor-erythroid-2-related factor 2)...
  43. Yu V, Gauthier C, St Arnaud R. Inhibition of ATF4 transcriptional activity by FIAT/gamma-taxilin modulates bone mass accrual. Ann N Y Acad Sci. 2006;1068:131-42 pubmed
    The basic domain-leucine zipper protein, activating transcription factor 4 (ATF4), was recently shown to control key aspects of osteoblast biology...
  44. Lange P, Chavez J, Pinto J, Coppola G, Sun C, Townes T, et al. ATF4 is an oxidative stress-inducible, prodeath transcription factor in neurons in vitro and in vivo. J Exp Med. 2008;205:1227-42 pubmed publisher
    ..In an in vitro model of oxidative stress, the expression of the bZip transcription factor activating transcription factor 4 (ATF4) was induced by glutathione depletion and localized to the promoter of a putative death gene ..
  45. Liu G, Su L, Hao X, Zhong N, Zhong D, Singhal S, et al. Salermide up-regulates death receptor 5 expression through the ATF4-ATF3-CHOP axis and leads to apoptosis in human cancer cells. J Cell Mol Med. 2012;16:1618-28 pubmed publisher
    ..This study highlights the importance of DR5 up-regulation in apoptosis induced by Sirt1/2 inhibition and elucidates the underlying mechanism in human NSCLC cells. ..
  46. Li H, Meng Q, Xiao F, Chen S, Du Y, Yu J, et al. ATF4 deficiency protects mice from high-carbohydrate-diet-induced liver steatosis. Biochem J. 2011;438:283-9 pubmed publisher
    ..ATF4 (activating transcription factor 4) has been shown to play an important role in the regulation of glucose metabolism and obesity ..
  47. Galehdar Z, Swan P, Fuerth B, Callaghan S, Park D, Cregan S. Neuronal apoptosis induced by endoplasmic reticulum stress is regulated by ATF4-CHOP-mediated induction of the Bcl-2 homology 3-only member PUMA. J Neurosci. 2010;30:16938-48 pubmed publisher
    ..through a p53-independent mechanism mediated by the ER-stress-inducible transcription factor ATF4 (activating transcription factor 4)...
  48. Ord D, Meerits K, Ord T. TRB3 protects cells against the growth inhibitory and cytotoxic effect of ATF4. Exp Cell Res. 2007;313:3556-67 pubmed
    ..We and other researchers have previously shown that TRB3 interacts with activating transcription factor 4 (ATF4) and may function as a negative feedback regulator of ATF4...
  49. Rouschop K, van den Beucken T, Dubois L, Niessen H, Bussink J, Savelkouls K, et al. The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Invest. 2010;120:127-41 pubmed publisher
    ..Our data therefore demonstrate that the UPR is an important mediator of the hypoxic tumor microenvironment and that it contributes to resistance to treatment through its ability to facilitate autophagy. ..
  50. Armstrong J, Flockhart R, Veal G, Lovat P, Redfern C. Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells. J Biol Chem. 2010;285:6091-100 pubmed publisher
  51. Milani M, Rzymski T, Mellor H, Pike L, Bottini A, Generali D, et al. The role of ATF4 stabilization and autophagy in resistance of breast cancer cells treated with Bortezomib. Cancer Res. 2009;69:4415-23 pubmed publisher
  52. Oskolkova O, Afonyushkin T, Leitner A, von Schlieffen E, Gargalovic P, Lusis A, et al. ATF4-dependent transcription is a key mechanism in VEGF up-regulation by oxidized phospholipids: critical role of oxidized sn-2 residues in activation of unfolded protein response. Blood. 2008;112:330-9 pubmed publisher
  53. Mamady H, Storey K. Coping with the stress: expression of ATF4, ATF6, and downstream targets in organs of hibernating ground squirrels. Arch Biochem Biophys. 2008;477:77-85 pubmed publisher
    ..The data suggest that ATF4 up-regulation may play an important role in coordinating gene expression responses that support the hibernating phenotype...