TGF-β1-induced cardiac myofibroblasts are nonproliferating functional cells carrying DNA damages

Experimental Cell Research

Volumn 314, Issue 7, 2008, Pages 1480-1494

  Petrov, Victor V ^a   van Pelt, Jos F ^a   Vermeesch, Joris R ^a   Van Duppen, Viktor J ^a   Vekemans, Katrien ^a   Fagard, Robert H ^a   Lijnen, Paul J ^a  

^a UNIVERSITY OF LEUVEN   (Belgium)

Author keywords

Apoptosis; Cell cycle; Cell differentiation; Cell proliferation; Collagen matrix contraction; Cytoskeleton; DNA damage; DNA repair; DNA synthesis; Flow cytometry; Lysyl oxidase; Myofibroblasts; Telomerase; TGF 1

Indexed keywords

CELL NUCLEUS ANTIGEN; PROTEIN LYSINE 6 OXIDASE; PROTEIN MAD1; SMAD1 PROTEIN; TELOMERASE; TRANSFORMING GROWTH FACTOR BETA1; BETA GALACTOSIDASE; COLLAGEN; CYCLIN DEPENDENT KINASE INHIBITOR 2A; CYCLIN DEPENDENT KINASE INHIBITOR 2B; CYCLINE; KI 67 ANTIGEN;

ANIMAL CELL; ARTICLE; CELL CYCLE G1 PHASE; CELL CYCLE S PHASE; CELL DIFFERENTIATION; CELL PROLIFERATION; CELL STRUCTURE; CONTROLLED STUDY; DNA DAMAGE; DNA FRAGMENTATION; ELECTROPHORESIS; FLOW CYTOMETRY; IMMUNOHISTOCHEMISTRY; MYOFIBROBLAST; NICK END LABELING; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; RAT; WESTERN BLOTTING; AGAR GEL ELECTROPHORESIS; ANIMAL; CYTOLOGY; DRUG EFFECT; ENZYMOLOGY; FIBROBLAST; HEART MUSCLE; MALE; METABOLISM; WISTAR RAT;

ANIMALS; BETA-GALACTOSIDASE; CELL PROLIFERATION; COLLAGEN; CYCLIN-DEPENDENT KINASE INHIBITOR P15; CYCLIN-DEPENDENT KINASE INHIBITOR P16; DNA DAMAGE; DNA FRAGMENTATION; ELECTROPHORESIS, AGAR GEL; FIBROBLASTS; G1 PHASE; IN SITU NICK-END LABELING; KI-67 ANTIGEN; MALE; MYOCARDIUM; PROLIFERATING CELL NUCLEAR ANTIGEN; PROTEIN-LYSINE 6-OXIDASE; RATS; RATS, WISTAR; SMAD1 PROTEIN; TELOMERASE; TRANSFORMING GROWTH FACTOR BETA1;

EID: 40949102618     PISSN: 00144827     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.yexcr.2008.01.014     Document Type: Article

References (92)

1. Leslie K.O., Taatjes D.J., Schwarz J., vonTurkovich M., and Low R.B. Cardiac myofibroblasts express alpha smooth muscle actin during right ventricular pressure overload in the rabbit. Am. J. Pathol. 139 (1991) 207-216
2. Nakamura T., Matsumoto K., Mizuno S., Sawa Y., Matsuda H., and Nakamura T. Hepatocyte growth factor prevents tissue fibrosis, remodeling, and dysfunction in cardiomyopathic hamster hearts. Am. J. Physiol. 288 (2005) H2131-H2139
3. Cleutjens J.P., Verluyten M.J., Smiths J.F., and Daemen M.J. Collagen remodeling after myocardial infarction in the rat heart. Am. J. Pathol. 147 (1995) 325-338
4. Willems I.E., Havenith M.G., De Mey J.G., and Daemen M.J. The α-smooth muscle actin-positive cells in healing human myocardial scars. Am. J. Pathol. 145 (1994) 868-875
5. Virag J.I., and Murry C.E. Myofibroblast and endothelial cell proliferation during murine myocardial infarct repair. Am. J. Pathol. 163 (2003) 2433-2440
6. Kamalov G., Varma B.R., Lu L., Sun Y., Weber K.T., and R.V. Guntaka. Expression of the multifunctional Y-box protein, YB-1, in myofibroblasts of the infarcted rat heart. Biochem. Biophys. Res. Commun. 334 (2005) 239-244
7. Katwa L.C. Cardiac myofibroblasts isolated from the site of myocardial infarction express endothelin de novo. Am. J. Physiol. 285 (2003) H1132-H1139
8. Hayakawa K., Takemura G., Kanoh M., Li Y., Koda M., Kawase Y., Maruyama R., Okada H., Minatoguchi S., Fujiwara T., and Fujiwara H. Inhibition of granulation tissue cell apoptosis during the subacute stage of myocardial infarction improves cardiac remodeling and dysfunction at the chronic stage. Circulation 108 (2003) 104-109
9. Sun Y., and Weber K.T. Infarct scar: a dynamic tissue. Cardiovasc. Res. 46 (2000) 250-256
10. Massague J., Blain S.W., and Lo R.S. TGF-β signaling in growth control, cancer, and heritable disorders. Cell 103 (2000) 295-309
11. Desmouliere A., Geinoz A., Gabbiani F., and Gabbiani G. Transforming growth factor-β 1 induces α-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J. Cell Biol. 122 (1993) 103-111
12. Untergasser G., Gander R., Rumpold H., Heinrich E., Plas E., and Berger P. TGF-β cytokines increase senescence-associated beta-galactosidase activity in human prostate basal cells by supporting differentiation processes, but not cellular senescence. Exp. Gerontol. 38 (2003) 1179-1188
13. Dimri G.P., Lee X., Basile G., Acosta M., Scott G., Roskelley C., Medrano E.E., Linskens M., Rubelj I., and Pereira-Smith O. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl. Acad. Sci. U. S. A. 92 (1995) 9363-9367
14. Hu B., Tack D.C., Liu T., Wu Z., Ullenbruch M.R., and Phan S.H. Role of Smad3 in the regulation of rat telomerase reverse transcriptase by TGFb. Oncogene 25 (2006) 1030-1041
15. Sanchez-Capelo A. Dual role for TGF-beta1 in apoptosis. Cytokine Growth Factor Rev. 16 (2005) 15-34
16. Petrov V.V., Fagard R.H., and Lijnen P.J. Stimulation of collagen production by transforming growth factor-beta1 during differentiation of cardiac fibroblasts to myofibroblasts. Hypertension 39 (2002) 258-263
17. Petrov V.V., Fagard R.H., and Lijnen P.J. Transforming growth factor-beta(1) induces angiotensin-converting enzyme synthesis in rat cardiac fibroblasts during their differentiation to myofibroblasts. J. Renin Angiotensin Aldosterone Syst. 1 (2000) 342-352
18. van Pelt J.F., Severi T., Crabbe T., Eetveldt A.V., Verslype C., Roskams T., and Fevery J. Expression of hepatitis C virus core protein impairs DNA repair in human hepatoma cells. Cancer Lett. 209 (2004) 197-205
19. Wang J., Zohar R., and McCulloch C.A. Multiple roles of α-smooth muscle actin in mechanotransduction. Exp. Cell Res. 312 (2006) 205-214
20. Tomasek J.J., Gabbiani G., Hinz B., Chaponnier C., and Brown R.A. Myofibroblasts and mechano-regulation of connecting tissue remodeling. Nat. Rev., Mol. Cell Biol. 3 (2007) 349-363
21. Darzynkiewicz Z., and Juan G. DNA content measurement for DNA ploidy and cell cycle analysis. In: Robison J.R., Darzynkiewicz Z., Dean P.N., Dressler L.P., Rabinowitch P.C., Stewart C.C., Tanke H.J., and Wheeless L.L. (Eds). Control protocols in cytometry, ISAC (1997) 7.5.1-7.5.24
22. Palamakumbura A.H., and Trackman P.C. A fluorometric assay for detection of lysyl oxidase enzyme activity in biological samples. Anal. Biochem. 300 (2002) 245-251
23. Lijnen P., Petrov V., Rumilla K., and Fagard R. Stimulation of collagen gel contraction by angiotensin II and III in cardiac fibroblasts. J. Renin Angiotensin. Aldosterone. Syst. 3 (2002) 160-166
24. Nakagawa S., Pawelek P., and Grinnell F. Extracellular matrix organization modulates fibroblast growth and growth factor responsiveness. Exp. Cell Res. 182 (1989) 572-582
25. Vermeesch J.R., Thoelen R., Salden I., Raes M., Matthijs G., and Fryns J.P. Mosaicism del(8p)/inv dup(8p) in a dysmorphic female infant: a mosaic formed by a meiotic error at the 8p OR gene and an independent terminal deletion event. J. Med. Genet. 40 (2003) e93
26. Wang J., Chen H., Seth A., and McCulloch C.A. Mechanical force regulation of myofibroblast differentiation in cardiac fibroblasts. Am. J. Physiol. 285 (2003) H1871-H1881
27. Colombo F., Gosselin H., El Helou V., and Calderone A. β-Adrenergic receptor-mediated DNA synthesis in neonatal rat cardiac fibroblasts proceeds via a phosphatidylinositol 3-kinase dependent pathway refractory to the antiproliferative action of cyclic AMP. J. Cell. Physiol. 195 (2003) 322-330
28. Chilton L., Ohya S., Freed D., George E., Drobic V., Shibukawa Y., Maccannell K.A., Imaizumi Y., Clark R.B., Dixon I.M., and Giles W.R. K+ currents regulate the resting membrane potential, proliferation, and contractile responses in ventricular fibroblasts and myofibroblasts. Am. J. Physiol. 288 (2005) H2931-H2939
29. Walker G.A., Masters K.S., Shah D.N., Anseth K.S., and Leinwand L.A. Valvular myofibroblast activation by transforming growth factor-β: implications for pathological extracellular matrix remodeling in heart valve disease. Circ. Res. 95 (2004) 253-260
30. Holt S.E., Wright W.E., and Shay J.W. Regulation of telomerase activity in immortal cell lines. Mol. Cell. Biol. 16 (1996) 2932-2939
31. Masur S.K., Dewal H.S., Dinh T.T., Erenburg I., and Petridou S. Myofibroblasts differentiate from fibroblasts when plated at low density. Proc. Natl. Acad. Sci. U. S. A. 93 (1996) 4219-4223
32. Fan L., Sebe A., Peterfi Z., Masszi A., Thirone A.C.P., Rotstein O.D., Nakano H., McCulloch C.A., Szaszi K., Mucsi I., and Kapus A. Cell contact-dependent regulation of epithelial-myofibroblast transition via the Rho-Rho kinase-phospho-myosin pathway. Mol. Biol. Cell 18 (2007) 1083-1097
33. Khouw I.M., van Wachem P.B., Plantinga J.A., Vujaskovic Z., Wissink M.J., de Leij L.F., and van Luyn M.J. TGF-β and bFGF affect the differentiation of proliferating porcine fibroblasts into myofibroblasts in vitro. Biomaterials 20 (1999) 1815-1822
34. Masui T., Wakefield L.M., Lechner J.F., LaVeck M.A., Sporn M.B., and Harris C.C. Type β transforming growth factor is the primary differentiation-inducing serum factor for normal human bronchial epithelial cells. Proc. Natl. Acad. Sci. U. S. A. 83 (1986) 2438-2442
35. Gospodarowicz D., Greenburg G., Bialecki H., and Zetter B.R. Factors involved in the modulation of cell proliferation in vivo and in vitro: the role of fibroblast and epidermal growth factors in the proliferative response of mammalian cells. In Vitro 14 (1978) 85-118
36. Borel F., Lacroix F.B., and Margolis R.L. Prolonged arrest of mammalian cells at the G1/S boundary results in permanent S phase stasis. J. Cell Sci. 115 (2002) 2829-2838
37. Toschi L., and Bravo R. Changes in cyclin/proliferating cell nuclear antigen distribution during DNA repair synthesis. J. Cell Biol. 107 (1988) 1623-1628
38. Lindahl T., and Wood R.D. Quality control by DNA repair. Science 286 (1999) 1897-1905
39. Sawhney N., and Hall P.A. Ki67-structure, function, and new antibodies. J. Pathol. 168 (1992) 161-162
40. Karlseder J., Smogorzewska A., and de Lange T. Senescence induced by altered telomere state, not telomere loss. Science 295 (2002) 2446-2449
41. Liu T., Hu B., Chung M.J., Ullenbruch M., Jin H., and Phan S.H. Telomerase regulation of myofibroblast differentiation. Am. J. Respir. Cell Mol. Biol. 34 (2006) 625-633
42. Untergasser G., Gander R., Lilg C., Lepperdinger G., Plas E., and Berger P. Profiling molecular targets of TGF-β1 in prostate fibroblast-to-myofibroblast transdifferentiation. Mech. Ageing Dev. 126 (2005) 59-69
43. Werner S., Beer H.D., Mauch C., Luscher B., and Werner S. The Mad1 transcription factor is a novel target of activin and TGF-β action in keratinocytes: possible role of Mad1 in wound repair and psoriasis. Oncogene 20 (2001) 7494-7504
44. Grandori C., Cowley S.M., James L.P., and Eisenman R.N. The Myc/Max/Mad network and the transcriptional control of cell behavior. Annu. Rev. Cell Dev. Biol. 16 (2000) 653-699
45. Chin L., Schreiber-Agus N., Pellicer I., Chen K., Lee H.W., Dudast M., Cordon-Cardo C., and DePinho R.A. Contrasting roles for Myc and Mad proteins in cellular growth and differentiation. Proc. Natl. Acad. Sci. U. S. A. 92 (1995) 8488-8492
46. Wang Y., Toury R., Hauchecorne M., and Balmain N. Expression and subcellular localization of the Myc superfamily proteins: c-Myc, Max, Mad1 and Mxi1 in the epiphyseal plate cartilage chondrocytes of growing rats. Cell. Mol. Biol. 43 (1997) 175-188
47. Johnstone A.P., and Williams G.T. Role of DNA breaks and ADP-ribosyl transferase activity in eukaryotic differentiation demonstrated in human lymphocytes. Nature 300 (1982) 368-370
48. Sjakste N., and Sjakste T. Possible involvement of DNA strand breaks in regulation of cell differentiation. Eur. J. Histochem. 51 (2007) 81-94
49. Tabocchini M.A., Rothkamm K., Signoretti C., Risse J., Sapora O., and Lobrich M. Formation and repair of DNA double-strand breaks in gamma-irradiated K562 cells undergoing erythroid differentiation. Mutat. Res. 461 (2000) 71-82
50. McMahon G., Alsina J.L., and Levy S.B. Induction of a Ca2+, Mg2+-dependent endonuclease activity during the early stages of murine erythroleukemic cell differentiation. Proc. Natl. Acad. Sci. U. S. A. 81 (1984) 7461-7465
51. Hristoskova S., Holzgreve W., and Hahn S.R.C. The chromatin of differentiating erythroblasts is cleaved into large size fragments independent of capase activated DNase and apoptosis inducing factor. J. Cell. Physiol. 213 (2007) 490-494
52. Kockx M.M., Muhring J., Knaapen M.W., and de Meyer G.R. RNA synthesis and splicing interferes with DNA in situ end labeling techniques used to detect apoptosis. Am. J. Pathol. 152 (1998) 885-888
53. Coates P.J., Save V., Ansari B., and Hall P.A. Demonstration of DNA damage/repair in individual cells using in situ end labelling: association of p53 with sites of DNA damage. J. Pathol. 176 (1995) 19-26
54. Yaoita H., Ogawa K., Maehara K., and Maruyama Y. Apoptosis in relevant clinical situations: contribution of apoptosis in myocardial infarction. Cardiovasc. Res. 45 (2000) 630-641
55. Caulin C., Salvesen G.S., and Oshima R.G. Caspase cleavage of keratin 18 and reorganization of intermediate filaments during epithelial cell apoptosis. J. Cell Biol. 138 (1997) 1379-1394
56. Leers M.P., Kolgen W., Bjorklund V., Bergman T., Tribbick G., Persson B., Bjorklund P., Ramaekers F.C., Bjorklund B., Nap M., Jornvall H., and Schutte B. Immunocytochemical detection and mapping of a cytokeratin 18 neo-epitope exposed during early apoptosis. J. Pathol. 187 (1999) 567-572
57. Oh S., Song Y.H., Yim J., and Kim T.K. Identification of Mad as a repressor of the human telomerase (hTERT) gene. Oncogene 19 (2000) 1485-1490
58. Lin S.Y., and Elledge S.J. Multiple tumor suppressor pathways negatively regulate telomerase. Cell 113 (2003) 881-889
59. Li H., Xu D., Li J., Berndt M.C., and Liu J.P. Transforming growth factor β suppresses human telomerase reverse transcriptase (hTERT) by Smad3 interactions with c-Myc and the hTERT gene. J. Biol. Chem. 281 (2006) 25588-25600
60. Hu B., Wu Z., and Phan S.H. Smad3 mediates transforming growth factor-beta-induced alpha-smooth muscle actin expression. Am. J. Respir. Cell Mol. Biol. 29 (2003) 397-404
61. Shen H., Fan J., Burczynski F., Minuk G.Y., Cattini P., and Gong Y. Increased Smad1 expression and transcriptional activity enhances trans-differentiation of hepatic stellate cells. J. Cell. Physiol. 212 (2007) 764-770
62. Attisano L., and Wrana J.L. Mads and Smads in TGF beta signalling. Curr. Opin. Cell Biol. 10 (1998) 188-194
63. Liu X., Yue J., Frey R.S., Zhu Q., and Mulder K.M. Transforming growth factor beta signaling through Smad1 in human breast cancer cells. Cancer Res. 58 (1998) 4752-4757
64. Hautmann M.B., Madsen C.S., and Owens G.K. A transforming growth factor beta (TGFbeta) control element drives TGFbeta-induced stimulation of smooth muscle alpha-actin gene expression in concert with two CArG elements. J. Biol. Chem. 272 (1997) 10948-10956
65. Takeda K., Gosiewska A., and Peterkofsky B. Similar, but not identical, modulation of expression of extracellular matrix components during in vitro and in vivo aging of human skin fibroblasts. J. Cell. Physiol. 153 (1992) 450-459
66. Hildebran J.N., Absher M., and Low R.B. Altered rates of collagen synthesis in in vitro aged human lung fibroblasts. In Vitro 19 (1983) 307-314
67. Zhu X., Kumar R., Mandal M., Sharma N., Sharma H.W., Dhingra U., Sokoloski J.A., Hsiao R., and Narayanan R. Cell cycle-dependent modulation of telomerase activity in tumor cells. Proc. Natl. Acad. Sci. U. S. A. 93 (1996) 6091-6095
68. Kanoh M., Takemura G., Misao J., Hayakawa Y., Aoyama T., Nishigaki K., Noda T., Fujiwara T., Fukuda K., Minatoguchi S., and Fujiwara H. Significance of myocytes with positive DNA in situ nick end-labeling (TUNEL) in hearts with dilated cardiomyopathy: not apoptosis but DNA repair. Circulation 99 (1999) 2757-2764
69. Kockx M.M. Apoptosis in the atherosclerotic plaque: quantitative and qualitative aspects. Arterioscler. Thromb. Vasc. Biol. 18 (1998) 1519-1522
70. Solov'yan V.T., Andreev I.O., Kolotova T.Y., Pogribniy P.V., Tarnavsky D.T., and Kunakh V.A. The cleavage of nuclear DNA into high molecular weight DNA fragments occurs not only during apoptosis but also accompanies changes in functional activity of the nonapoptotic cells. Exp. Cell Res. 235 (1997) 130-137
71. Szabo Jr. G. 50-kb chromatin fragmentation in the absence of apoptosis. Exp. Cell Res. 221 (1995) 320-325
72. Darzynkiewicz Z., Juan G., Li X., Gorczyca W., Murakami T., and Traganos F. Cytometry in cell necrobiology: analysis of apoptosis and accidental cell death (necrosis). Cytometry 27 (1997) 1-20
73. Oberhammer F., Wilson J.W., Dive C., Morris I.D., Hickman J.A., Wakeling A.E., Walker P.R., and Sikorska M. Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation. EMBO J. 12 (1993) 3679-3684
74. McIlroy D., Sakahira H., Talanian R.V., and Nagata S. Involvement of caspase 3-activated DNase in internucleosomal DNA cleavage induced by diverse apoptotic stimuli. Oncogene 18 (1999) 4401-4408
75. Formici P., Radi E., Battisti C., Tarquini E., Leonini A., Di Stefano A., and Federico A. Human fibroblasts undergo oxidative stress-induced apoptosis without internucleosomal DNA fragmentation. J. Cell. Physiol. 208 (2006) 289-297
76. Matsubara K., Kubota M., Adachi S., Kuwakado K., Hirota H., Wakazono Y., Akiyama Y., and Mikawa H. Induction of apoptosis in childhood acute leukemia by chemotherapeutic agents: failure to detect evidence of apoptosis in vivo. Eur. J. Haematol. 52 (1994) 47-52
77. Collins R.J., Harmon B.V., Gobe G.C., and Kerr J.F. Internucleosomal DNA cleavage should not be the sole criterion for identifying apoptosis. Int. J. Radiat. Biol. 61 (1992) 451-453
78. Barres B.A., Hart I.K., Coles H.S., Burne J.F., Voyvodic J.T., Richardson W.D., and Raff M.C. Cell death and control of cell survival in the oligodendrocyte lineage. Cell 70 (1992) 31-46
79. Oberhammer F., Fritsch G., Schmied M., Pavelka M., Printz D., Purchio T., Lassmann H., and Schulte-Hermann R. Condensation of the chromatin at the membrane of an apoptotic nucleus is not associated with activation of an endonuclease. J. Cell Sci. 104 Pt 2 (1993) 317-326
80. Bahl N., Zhang J., Llovera M., Ballester M., Comella J.X., and Sanchis D. Switch from caspase-dependent to caspase-independent death during heart development. Essential role of endonuclease G in ischemia-induced DNA processing of differentiated cardiomyocytes. J. Biol. Chem. 281 (2006) 22943-22952
81. Cao Y., Chen L., Zhang W., Liu Y., Papaconstantinou H.T., Bush C.R., Townsend Jr. C.M., Thompson E.A., and Ko T.C. Identification of apoptotic genes mediating TGF-β/Smad3-induced cell death in intestinal epithelial cells using a genomic approach. Am. J. Physiol. 292 (2007) G28-G38
82. Pandey S., and Wang E. Cells en route to apoptosis are characterized by the upregulation of c-fos, c-myc, c-jun, cdc2, and RB phosphorylation, resembling events of early cell-cycle traverse. J. Cell. Biochem. 58 (1995) 135-150
83. Farzaneh F., Zalin R., Brill D., and Shall S. DNA strand breaks and ADP-ribosyl transferase activation during cell differentiation. Nature 300 (1982) 362-366
84. de La Roche Saint-Andre. Tails and cuts: the role of histone post-translational modifications in the formation of programmed double-strand breaks. Biochimie 87 (2005) 603-612
85. Farzaneh F., Meldrum R., and Shall S. Transient formation of DNA strand breaks during the induced differentiation of a human promyelocytic leukaemic cell line, HL-60. Nucleic Acids Res. 15 (1987) 3493-3502
86. Latella L., Lukas J., Simone C., Puri P.L., and Bartek J. Differentiation-induced radioresistance in muscle cells. Mol. Cell. Biol. 24 (2004) 6350-6361
87. Solary E., Bertrand R., Kohn K.W., and Pommier Y. Differential induction of apoptosis in undifferentiated and differentiated HL-60 cells by DNA topoisomerase I and II inhibitors. Blood 81 (1993) 1359-1368
88. Xie G., Habbersett R.C., Jia Y., Peterson S.R., Lehnert B.E., Bradbury E.M., and D'Anna J.A. Requirements for p53 and the ATM gene product in the regulation of G1/S and S phase checkpoints. Oncogene 16 (1998) 721-736
89. Sancar A., Lindsey-Boltz L.A., Unsal-Kacmaz K., and Linn S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Ann. Rev. Biochem. 73 (2004) 39-85
90. Narula N., Narula J., Zhang P.J., Haider N., Raghunath P.N., Brittin R., Gorman III J.H., Gorman R.C., and Tomaszewski J.E. Is the myofibrillarlytic myocyte a forme fruste apoptotic myocyte?. Ann. Thorac. Surg. 79 (2005) 1333-1337
91. Roussel M.F., Ashmun R.A., Sherr C.J., Eisenman R.N., and Ayer D.E. Inhibition of cell proliferation by the Mad1 transcriptional repressor. Mol. Cell. Biol. 16 (1996) 2796-2801
92. Hannon G.J., and Beach D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 371 (1994) 257-261