title: Myeloid leukemia factor-1 is a novel modulator of neonatal rat cardiomyocyte proliferation.
abstract: The present study focuses on the identification of the gene expression profile of neonatal rat cardiomyocytes (NRVCMs) after dynamic mechanical stretch through microarrays of RNA isolated from cells stretched for 2, 6 or 24h. In this analysis, myeloid leukemia factor-1 (MLF1) was found to be significantly downregulated during the course of stretch. We found that MLF1 is highly expressed in the heart, however, its cardiac function is unknown yet. In line with microarray data, MLF1 was profoundly downregulated in in vivo mouse models of cardiomyopathy, and also significantly reduced in the hearts of human patients with dilated cardiomyopathy. Our data indicates that the overexpression of MLF1 in NRVCMs inhibited cell proliferation while augmenting apoptosis. Conversely, knockdown of MLF1 protected NRVCMs from apoptosis and promoted cell proliferation. Moreover, we found that knockdown of MLF1 protected NRVCMs from hypoxia-induced cell death. The observed accelerated apoptosis is attributed to the activation of caspase-3/-7/PARP-dependent apoptotic signaling and upregulation of p53. Most interestingly, MLF1 knockdown significantly upregulated the expression of D cyclins suggesting its possible role in cyclin-dependent cell proliferation. Taken together, we, for the first time, identified an important role for MLF1 in NRVCM proliferation.
authors.affiliation: Department of Internal Medicine III (Cardiology, Angiology, Intensive Care), University Medical Center Kiel, 24105 Kiel, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 24105 Kiel, Germany.
authors.forename: Ashraf Yusuf
authors.initials: AY
authors.lastname: Rangrez
authors.affiliation: Department of Internal Medicine III (Cardiology, Angiology, Intensive Care), University Medical Center Kiel, 24105 Kiel, Germany.
authors.forename: Jost
authors.initials: J
authors.lastname: Pott
authors.affiliation: Department of Internal Medicine III (Cardiology, Angiology, Intensive Care), University Medical Center Kiel, 24105 Kiel, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Kluge
authors.affiliation: University Medical Center Eppendorf, 20246 Hamburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Frauen
authors.affiliation: Department of Internal Medicine III (Cardiology, Angiology, Intensive Care), University Medical Center Kiel, 24105 Kiel, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Stiebeling
authors.affiliation: Department of Internal Medicine III (Cardiology, Angiology, Intensive Care), University Medical Center Kiel, 24105 Kiel, Germany.
authors.forename: Phillip
authors.initials: P
authors.lastname: Hoppe
authors.affiliation: Department of Internal Medicine III (Cardiology, Angiology, Intensive Care), University Medical Center Kiel, 24105 Kiel, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 24105 Kiel, Germany.
authors.forename: Samuel
authors.initials: S
authors.lastname: Sossalla
authors.affiliation: Department of Internal Medicine III (Cardiology, Angiology, Intensive Care), University Medical Center Kiel, 24105 Kiel, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 24105 Kiel, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Frey
authors.affiliation: Department of Internal Medicine III (Cardiology, Angiology, Intensive Care), University Medical Center Kiel, 24105 Kiel, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 24105 Kiel, Germany. Electronic address: derk.frank@uksh.de.
authors.forename: Derk
authors.initials: D
authors.lastname: Frank
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001696:Biomechanical Phenomena; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000235:genetics*; D056741:Cyclin D / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins; D020411:Oligonucleotide Array Sequence Analysis; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013314:Stress, Mechanical; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D056741:Cyclin D; D004268:DNA-Binding Proteins; C100852:MLF1 protein, human; C000623103:Mlf1 protein, rat; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011506:Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D011065:Poly(ADP-ribose) Polymerases; C505410:Casp3 protein, rat; D053148:Caspase 3
keywords: Apoptosis; Biomechanical stress; Caspase-3; D cyclins; Myeloid leukemia factor-1; Proliferation