Exercise and diabetes have opposite effects on the assembly and O-GlcNAc modification of the mSin3A/HDAC1/2 complex in the heart

Cardiovascular Diabetology

Volumn 12, Issue 1, 2013, Pages

  Cox, Emily J ^a   Marsh, Susan A ^a  

^a WASHINGTON STATE UNIVERSITY   (United States)

Author keywords

Cardiac hypertrophy; Diabetes; Exercise; Fetal genes; O GlcNAc

Indexed keywords

GLUCOSE; HISTONE DEACETYLASE 1; HISTONE DEACETYLASE 2; MESSENGER RNA; N ACETYLGLUCOSAMINE; O LINKED BETA N ACETYLGLUCOSAMINE; TRANSCRIPTION FACTOR SIN3A; UNCLASSIFIED DRUG; GLUCOSE BLOOD LEVEL; HDAC1 PROTEIN, MOUSE; HDAC2 PROTEIN, MOUSE; N ACETYLGLUCOSAMINYLTRANSFERASE; REPRESSOR PROTEIN; SIN3A TRANSCRIPTION FACTOR; UDP-N-ACETYLGLUCOSAMINE-PEPTIDE BETA-N-ACETYLGLUCOSAMINYLTRANSFERASE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BODY WEIGHT; CONTROLLED STUDY; DIET RESTRICTION; ENZYME ACTIVITY; GENE EXPRESSION; GENOTYPE; GLUCOSE BLOOD LEVEL; HEART VENTRICLE HYPERTROPHY; HYPERGLYCEMIA; IMMUNOPRECIPITATION; MOUSE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; SITTING; TREADMILL EXERCISE; ANIMAL; C57BL MOUSE; CARDIOMEGALY; DIABETES MELLITUS, TYPE 2; DIABETIC CARDIOMYOPATHIES; DISEASE MODEL; GENE EXPRESSION REGULATION; GENETICS; GLYCOSYLATION; HEART MUSCLE; KINESIOTHERAPY; METABOLISM; PROTEIN PROCESSING; RUNNING; SEDENTARY LIFESTYLE; TIME;

ACETYLGLUCOSAMINE; ANIMALS; BLOOD GLUCOSE; CARDIOMEGALY; DIABETES MELLITUS, TYPE 2; DIABETIC CARDIOMYOPATHIES; DISEASE MODELS, ANIMAL; EXERCISE THERAPY; GENE EXPRESSION REGULATION; GLYCOSYLATION; HISTONE DEACETYLASE 1; HISTONE DEACETYLASE 2; MICE, INBRED C57BL; MYOCARDIUM; N-ACETYLGLUCOSAMINYLTRANSFERASES; OBESITY; PROTEIN PROCESSING, POST-TRANSLATIONAL; REPRESSOR PROTEINS; RNA, MESSENGER; RUNNING; SEDENTARY LIFESTYLE; TIME FACTORS;

EID: 84880032308     PISSN: None     EISSN: 14752840     Source Type: Journal    
DOI: 10.1186/1475-2840-12-101     Document Type: Article

References (71)

1. Falcao-Pires I, Palladini G, Goncalves N, van der Velden J, Moreira-Goncalves D, Miranda-Silva D, Salinaro F, Paulus WJ, Niessen HW, Perlini S, Leite-Moreira AF. Distinct mechanisms for diastolic dysfunction in diabetes mellitus and chronic pressure-overload. Basic Res Cardiol 2011, 106:801-814. 10.1007/s00395-011-0184-x, 21533831.
2. Watanabe M, Yokoshiki H, Mitsuyama H, Mizukami K, Ono T, Tsutsui H. Conduction and refractory disorders in the diabetic atrium. Am J Physiol Heart Circ Physiol 2012, 303:H86-H95. 10.1152/ajpheart.00010.2012, 22561303.
3. Carley AN, Severson DL. Fatty acid metabolism is enhanced in type 2 diabetic hearts. Biochim Biophys Acta 2005, 1734:112-126. 10.1016/j.bbalip.2005.03.005, 15904868.
4. Chess DJ, Stanley WC. Role of diet and fuel overabundance in the development and progression of heart failure. Cardiovasc Res 2008, 79:269-278. 10.1093/cvr/cvn074, 18343896.
5. Boudina S, Abel ED. Diabetic cardiomyopathy, causes and effects. Rev Endocr Metab Disord 2010, 11:31-39. 10.1007/s11154-010-9131-7, 2914514, 20180026.
6. Baggish AL, Yared K, Wang F, Weiner RB, Hutter AM, Picard MH, Wood MJ. The impact of endurance exercise training on left ventricular systolic mechanics. Am J Physiol Heart Circ Physiol 2008, 295:H1109-H1116. 10.1152/ajpheart.00395.2008, 18621855.
7. Vinereanu D, Florescu N, Sculthorpe N, Tweddel AC, Stephens MR, Fraser AG. Differentiation between pathologic and physiologic left ventricular hypertrophy by tissue Doppler assessment of long-axis function in patients with hypertrophic cardiomyopathy or systemic hypertension and in athletes. Am J Cardiol 2001, 88:53-58. 10.1016/S0002-9149(01)01585-5, 11423058.
8. Gertz EW, Wisneski JA, Stanley WC, Neese RA. Myocardial substrate utilization during exercise in humans. Dual carbon-labeled carbohydrate isotope experiments. J Clin Invest 1988, 82:2017-2025. 10.1172/JCI113822, 442784, 3198763.
9. Bergman BC, Tsvetkova T, Lowes B, Wolfel EE. Myocardial FFA metabolism during rest and atrial pacing in humans. Am J Physiol Endocrinol Metab 2009, 296:E358-E366. 2645020, 19066320.
10. Loganathan R, Bilgen M, Al-Hafez B, Zhero SV, Alenezy MD, Smirnova IV. Exercise training improves cardiac performance in diabetes: in vivo demonstration with quantitative cine-MRI analyses. J Appl Physiol 2007, 102:665-672.
11. Broderick TL, Poirier P, Gillis M. Exercise training restores abnormal myocardial glucose utilization and cardiac function in diabetes. Diabetes Metab Res Rev 2005, 21:44-50. 10.1002/dmrr.479, 15386820.
12. Stolen KQ, Kemppainen J, Ukkonen H, Kalliokoski KK, Luotolahti M, Lehikoinen P, Hämäläinen H, Salo T, Airaksinen KE, Nuutila P, Knuuti J. Exercise training improves biventricular oxidative metabolism and left ventricular efficiency in patients with dilated cardiomyopathy. J Am Coll Cardiol 2003, 41:460-467.
13. Stolen TO, Hoydal MA, Kemi OJ, Catalucci D, Ceci M, Aasum E, Larsen T, Rolim N, Condorelli G, Smith GL, Wisloff U. Interval training normalizes cardiomyocyte function, diastolic Ca2+ control, and SR Ca2+ release synchronicity in a mouse model of diabetic cardiomyopathy. Circ Res 2009, 105:527-536. 10.1161/CIRCRESAHA.109.199810, 19679837.
14. Hafstad AD, Lund J, Hadler-Olsen E, Hoper AC, Larsen TS, Aasum E. High- and Moderate-Intensity Training Normalizes Ventricular Function and Mechanoenergetics in Mice With Diet-Induced Obesity. Diabetes 2013, 62:2287-2294. 10.2337/db12-1580, 23493573.
15. Rosenkranz AC, Hood SG, Woods RL, Dusting GJ, Ritchie RH. B-type natriuretic peptide prevents acute hypertrophic responses in the diabetic rat heart: importance of cyclic GMP. Diabetes 2003, 52:2389-2395. 10.2337/diabetes.52.9.2389, 12941780.
16. Gao XR, Tan YZ, Wang HJ. Overexpression of Csx/Nkx2.5 and GATA-4 enhances the efficacy of mesenchymal stem cell transplantation after myocardial infarction. Circ J 2011, 75:2683-2691. 10.1253/circj.CJ-11-0238, 21828931.
17. Franco V, Chen YF, Oparil S, Feng JA, Wang D, Hage F, Perry G. Atrial natriuretic peptide dose-dependently inhibits pressure overload-induced cardiac remodeling. Hypertension 2004, 44:746-750. 10.1161/01.HYP.0000144801.09557.4c, 15452027.
18. Brattelid T, Qvigstad E, Moltzau LR, Bekkevold SV, Sandnes DL, Birkeland JA, Skomedal T, Osnes JB, Sjaastad I, Levy FO. The cardiac ventricular 5-HT4 receptor is functional in late foetal development and is reactivated in heart failure. PLoS One 2012, 7:e45489. 10.1371/journal.pone.0045489, 3447799, 23029047.
19. Azakie A, Fineman JR, He Y. Myocardial transcription factors are modulated during pathologic cardiac hypertrophy in vivo. J Thorac Cardiovasc Surg 2006, 132:1262-1271. 10.1016/j.jtcvs.2006.08.005, 17140938.
20. Kuwahara K, Nishikimi T, Nakao K. Transcriptional regulation of the fetal cardiac gene program. J Pharmacol Sci 2012, 119:198-203. 10.1254/jphs.12R04CP, 22786561.
21. Rajabi M, Kassiotis C, Razeghi P, Taegtmeyer H. Return to the fetal gene program protects the stressed heart: a strong hypothesis. Heart Fail Rev 2007, 12:331-343. 10.1007/s10741-007-9034-1, 17516164.
22. Chang L, Kiriazis H, Gao XM, Du XJ, El-Osta A. Cardiac genes show contextual SWI/SNF interactions with distinguishable gene activities. Epigenetics 2011, 6:760-768. 10.4161/epi.6.6.16007, 21586902.
23. Koitabashi N, Danner T, Zaiman AL, Pinto YM, Rowell J, Mankowski J, Zhang D, Nakamura T, Takimoto E, Kass DA. Pivotal role of cardiomyocyte TGF-beta signaling in the murine pathological response to sustained pressure overload. J Clin Invest 2011, 121:2301-2312. 10.1172/JCI44824, 3104748, 21537080.
24. Port JD, Walker LA, Polk J, Nunley K, Buttrick PM, Sucharov CC. Temporal expression of miRNAs and mRNAs in a mouse model of myocardial infarction. Physiol Genomics 2011, 43:1087-1095. 10.1152/physiolgenomics.00074.2011, 3217325, 21771878.
25. Burniston JG. Adaptation of the rat cardiac proteome in response to intensity-controlled endurance exercise. Proteomics 2009, 9:106-115. 10.1002/pmic.200800268, 19053138.
26. McMullen JR, Shioi T, Zhang L, Tarnavski O, Sherwood MC, Kang PM, Izumo S. Phosphoinositide 3-kinase(p110alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy. Proc Natl Acad Sci USA 2003, 100:12355-12360. 10.1073/pnas.1934654100, 218762, 14507992.
27. Gutkowska J, Broderick TL, Bogdan D, Wang D, Lavoie JM, Jankowski M. Downregulation of oxytocin and natriuretic peptides in diabetes: possible implications in cardiomyopathy. J Physiol 2009, 587:4725-4736. 10.1113/jphysiol.2009.176461, 2768025, 19675071.
28. Broderick TL, Jankowski M, Wang D, Danalache BA, Parrott CR, Gutkowska J. Downregulation in GATA4 and Downstream Structural and Contractile Genes in the db/db Mouse Heart. ISRN endocrinology 2012, 2012:736860. 3313578, 22474596.
29. Marsh SA, Dell'Italia LJ, Chatham JC. Activation of the hexosamine biosynthesis pathway and protein O-GlcNAcylation modulate hypertrophic and cell signaling pathways in cardiomyocytes from diabetic mice. Amino Acids 2011, 40:819-828. 10.1007/s00726-010-0699-8, 3025273, 20676904.
30. Ande SR, Moulik S, Mishra S. Interaction between O-GlcNAc modification and tyrosine phosphorylation of prohibitin: implication for a novel binary switch. PLoS One 2009, 4:e4586. 10.1371/journal.pone.0004586, 2642629, 19238206.
31. Hart GW, Akimoto Y. The O-GlcNAc Modification. Essentials of Glycobiology 2009, NY: Cold Spring Harbor, Varki A, Cummings RD, Esko JD, Freeze HH, Stanley P, Bertozzi CR, Hart GW, Etzler ME, 2.
32. Medford HM, Porter K, Marsh SA. Immediate effects of a single exercise bout on protein O-GlcNAcylation and chromatin regulation of cardiac hypertrophy. Am J Physiol Heart Circ Physiol 2013, 305(1):H114-H123. 10.1152/ajpheart.00135.2013, 23624624.
33. Roopra A, Sharling L, Wood IC, Briggs T, Bachfischer U, Paquette AJ, Buckley NJ. Transcriptional repression by neuron-restrictive silencer factor is mediated via the Sin3-histone deacetylase complex. Mol Cell Biol 2000, 20:2147-2157. 10.1128/MCB.20.6.2147-2157.2000, 110831, 10688661.
34. Kee HJ, Kook H. Roles and targets of class I and IIa histone deacetylases in cardiac hypertrophy. J Biomed Biotechnol 2011, 2011:928326. 2997602, 21151616.
35. Yang X, Zhang F, Kudlow JE. Recruitment of O-GlcNAc transferase to promoters by corepressor mSin3A: coupling protein O-GlcNAcylation to transcriptional repression. Cell 2002, 110:69-80. 10.1016/S0092-8674(02)00810-3, 12150998.
36. Shafi R, Iyer SP, Ellies LG, O'Donnell N, Marek KW, Chui D, Hart GW, Marth JD. The O-GlcNAc transferase gene resides on the X chromosome and is essential for embryonic stem cell viability and mouse ontogeny. Proc Natl Acad Sci USA 2000, 97:5735-5739. 10.1073/pnas.100471497, 18502, 10801981.
37. Kreppel LK, Hart GW. Regulation of a cytosolic and nuclear O-GlcNAc transferase. Role of the tetratricopeptide repeats. J Biol Chem 1999, 274:32015-32022. 10.1074/jbc.274.45.32015, 10542233.
38. Hu Y, Belke D, Suarez J, Swanson E, Clark R, Hoshijima M, Dillmann WH. Adenovirus-mediated overexpression of O-GlcNAcase improves contractile function in the diabetic heart. Circ Res 2005, 96:1006-1013. 10.1161/01.RES.0000165478.06813.58, 15817886.
39. Clark RJ, McDonough PM, Swanson E, Trost SU, Suzuki M, Fukuda M, Dillmann WH. Diabetes and the accompanying hyperglycemia impairs cardiomyocyte calcium cycling through increased nuclear O-GlcNAcylation. J Biol Chem 2003, 278:44230-44237. 10.1074/jbc.M303810200, 12941958.
40. Lunde IG, Aronsen JM, Kvaloy H, Qvigstad E, Sjaastad I, Tonnessen T, Christensen G, Gronning-Wang LM, Carlson CR. Cardiac O-GlcNAc signaling is increased in hypertrophy and heart failure. Physiol Genomics 2012, 44:162-172. 10.1152/physiolgenomics.00016.2011, 22128088.
41. Watson LJ, Facundo HT, Ngoh GA, Ameen M, Brainard RE, Lemma KM, Long BW, Prabhu SD, Xuan YT, Jones SP. O-linked beta-N-acetylglucosamine transferase is indispensable in the failing heart. Proc Natl Acad Sci USA 2010, 107:17797-17802. 10.1073/pnas.1001907107, 2955091, 20876116.
42. Jensen RV, Zachara NE, Nielsen PH, Kimose HH, Kristiansen SB, Botker HE. Impact of O-GlcNAc on cardioprotection by remote ischaemic preconditioning in non-diabetic and diabetic patients. Cardiovasc Res 2013, 97(2):369-378. 10.1093/cvr/cvs337, 23201773.
43. Belke DD. Swim-exercised mice show a decreased level of protein O-GlcNAcylation and expression of O-GlcNAc transferase in heart. J Appl Physiol 2011, 111:157-162. 10.1152/japplphysiol.00147.2011, 21493720.
44. Bennett CE, Johnsen VL, Shearer J, Belke DD. Exercise training mitigates aberrant cardiac protein O-GlcNAcylation in streptozotocin-induced diabetic mice. Life Sci 2013, 92(11):657-663. 10.1016/j.lfs.2012.09.007, 23000101.
45. Colberg SR, Sigal RJ, Fernhall B, Regensteiner JG, Blissmer BJ, Rubin RR, Chasan-Taber L, Albright AL, Braun B. American College of Sports M, American Diabetes A Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement. Diabetes Care 2010, 33:e147-e167. 10.2337/dc10-9990, 2992225, 21115758, American College of Sports M, American Diabetes A.
46. Schefer V, Talan MI. Oxygen consumption in adult and AGED C57 mice during acute treadmill exercise of different intensity. Exp Gerontol 1996, 31:387-392. 10.1016/0531-5565(95)02032-2, 9415121.
47. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001, 25:402-408. 10.1006/meth.2001.1262, 11846609.
48. Shearer J, Ross KD, Hughey CC, Johnsen VL, Hittel DS, Severson DL. Exercise training does not correct abnormal cardiac glycogen accumulation in the db/db mouse model of type 2 diabetes. Am J Physiol Endocrinol Metab 2011, 301:E31-E39. 10.1152/ajpendo.00525.2010, 21386062.
49. Lee S, Park Y, Zhang C. Exercise training prevents coronary endothelial dysfunction in type 2 diabetic mice. Am J Biomed Sci 2011, 3:241-252. 3289260, 22384308.
50. Bates SH, Stearns WH, Dundon TA, Schubert M, Tso AW, Wang Y, Banks AS, Lavery HJ, Haq AK, Maratos-Flier E, et al. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 2003, 421:856-859. 10.1038/nature01388, 12594516.
51. Mozaffari MS, Baban B, Abdelsayed R, Liu JY, Wimborne H, Rodriguez N, Abebe W. Renal and glycemic effects of high-dose chromium picolinate in db/db mice: assessment of DNA damage. J Nutr Biochem 2012, 23:977-985. 10.1016/j.jnutbio.2011.05.004, 21959055.
52. Pflum MK, Tong JK, Lane WS, Schreiber SL. Histone deacetylase 1 phosphorylation promotes enzymatic activity and complex formation. J Biol Chem 2001, 276:47733-47741. 10.1074/jbc.M105590200, 11602581.
53. Kuwahara K, Saito Y, Takano M, Arai Y, Yasuno S, Nakagawa Y, Takahashi N, Adachi Y, Takemura G, Horie M, et al. NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function. EMBO J 2003, 22:6310-6321. 10.1093/emboj/cdg601, 291842, 14633990.
54. Yi T, Cheema Y, Tremble SM, Bell SP, Chen Z, Subramanian M, LeWinter MM, VanBuren P, Palmer BM. Zinc-induced cardiomyocyte relaxation in a rat model of hyperglycemia is independent of myosin isoform. Cardiovasc Diabetol 2012, 11:135. 10.1186/1475-2840-11-135, 3537566, 23116444.
55. McGavock JM, Lingvay I, Zib I, Tillery T, Salas N, Unger R, Levine BD, Raskin P, Victor RG, Szczepaniak LS. Cardiac steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy study. Circulation 2007, 116:1170-1175. 10.1161/CIRCULATIONAHA.106.645614, 17698735.
56. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 2005, 85:1093-1129. 10.1152/physrev.00006.2004, 15987803.
57. Rijzewijk LJ, van der Meer RW, Smit JW, Diamant M, Bax JJ, Hammer S, Romijn JA, de Roos A, Lamb HJ. Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J Am Coll Cardiol 2008, 52:1793-1799. 10.1016/j.jacc.2008.07.062, 19022158.
58. Montgomery RL, Davis CA, Potthoff MJ, Haberland M, Fielitz J, Qi X, Hill JA, Richardson JA, Olson EN. Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Genes Dev 2007, 21:1790-1802. 10.1101/gad.1563807, 1920173, 17639084.
59. Thompson PD, Buchner D, Pina IL, Balady GJ, Williams MA, Marcus BH, Berra K, Blair SN, Costa F, Franklin B, et al. Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity). Circulation 2003, 107:3109-3116. 10.1161/01.CIR.0000075572.40158.77, 12821592.
60. Hordern MD, Coombes JS, Cooney LM, Jeffriess L, Prins JB, Marwick TH. Effects of exercise intervention on myocardial function in type 2 diabetes. Heart 2009, 95:1343-1349. 10.1136/hrt.2009.165571, 19429570.
61. Kazemi Z, Chang H, Haserodt S, McKen C, Zachara NE. O-linked beta-N-acetylglucosamine (O-GlcNAc) regulates stress-induced heat shock protein expression in a GSK-3beta-dependent manner. J Biol Chem 2010, 285:39096-39107. 10.1074/jbc.M110.131102, 2998145, 20926391.
62. Zachara NE, O'Donnell N, Cheung WD, Mercer JJ, Marth JD, Hart GW. Dynamic O-GlcNAc modification of nucleocytoplasmic proteins in response to stress. A survival response of mammalian cells. J Biol Chem 2004, 279:30133-30142. 10.1074/jbc.M403773200, 15138254.
63. Balakumar P, Sharma NK. Healing the diabetic heart: does myocardial preconditioning work?. Cell Signal 2012, 24:53-59. 10.1016/j.cellsig.2011.09.007, 21945408.
64. Nawata T, Takahashi N, Ooie T, Kaneda K, Saikawa T, Sakata T. Cardioprotection by streptozotocin-induced diabetes and insulin against ischemia/reperfusion injury in rats. J Cardiovasc Pharmacol 2002, 40:491-500. 10.1097/00005344-200210000-00001, 12352310.
65. Trivedi CM, Luo Y, Yin Z, Zhang M, Zhu W, Wang T, Floss T, Goettlicher M, Noppinger PR, Wurst W, et al. Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activity. Nat Med 2007, 13:324-331. 10.1038/nm1552, 17322895.
66. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol 1974, 34:29-34. 10.1016/0002-9149(74)90089-7, 4835750.
67. Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview. Lancet 2000, 355:773-778. 10.1016/S0140-6736(99)08415-9, 10711923.
68. Buchanan J, Mazumder PK, Hu P, Chakrabarti G, Roberts MW, Yun UJ, Cooksey RC, Litwin SE, Abel ED. Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology 2005, 146:5341-5349. 10.1210/en.2005-0938, 16141388.
69. Demarco VG, Ford DA, Henriksen EJ, Aroor AR, Johnson MS, Habibi J, Ma L, Yang M, Albert CJ, Lally JW, et al. Obesity-related alterations in cardiac lipid profile and nondipping blood pressure pattern during transition to diastolic dysfunction in male db/db mice. Endocrinology 2013, 154:159-171. 10.1210/en.2012-1835, 23142808.
70. Wong SS, Bernstein HS. Cardiac regeneration using human embryonic stem cells: producing cells for future therapy. Regen Med 2010, 5:763-775. 10.2217/rme.10.52, 2955159, 20868331.
71. Lagger G, O'Carroll D, Rembold M, Khier H, Tischler J, Weitzer G, Schuettengruber B, Hauser C, Brunmeir R, Jenuwein T, Seiser C. Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J 2002, 21:2672-2681. 10.1093/emboj/21.11.2672, 126040, 12032080.