title: Stress-specific responses of p21 expression: implication of transcript variant p21 alt-a in long-term hypoxia.
abstract: p21 (CDKN1A, Cip1, Waf1) is a cyclin-dependent kinase inhibitor capable of causing cell cycle arrest or promoting cell cycle transit as well as acting as a regulator of apoptosis. In this study, we analyzed the effects of various antemortem conditions on p21 protein level and expression profiles of known p21 transcript variants in human heart tissue. The selected death cause groups were: non-cardiac, hypothermia, acute ischemia, and chronic hypoxia. Immunohistochemical staining of p21 in cardiac myocytes could be observed only in hypothermia death cases, in which the mRNA expression of the most abundant variant, p21V1, also exceeded that in other death cause groups. Cytoplasmic localization of p21 protein in vascular smooth muscle cells together with substantially increased expression of cardioprotective Pim-1 especially in chronic hypoxia, but in acute ischemia and hypothermia as well, indicate change of p21 function from cell cycle arrest to promotion of proliferation and cell survival in these cases. In chronic hypoxia deaths the expression of variant p21 alt-a was highly pronounced whereas the expression of variant p21B was low. In chronic hypoxia deaths the expression of p53 was substantially higher compared to the other groups, being a potential regulator of p21 alt-a expression. In acute ischemia deaths increased expression of variant p21B, suggested to be proapoptotic in several cell lines, was observed. Our results suggest a role for variant p21 alt-a in hypoxia and for variant p21B in acute myocardial ischemia. The known cardioprotective aspect of hypothermia might come from an increased p21 protein level.
authors.affiliation: Institute of Diagnostics, Department of Forensic Medicine, P.O. Box 5000, University of Oulu, FI-90014 Oulu, Finland.
authors.forename: Helena M
authors.initials: HM
authors.lastname: Kaija
authors.forename: Terttu
authors.initials: T
authors.lastname: Särkioja
authors.forename: Marja-Leena
authors.initials: ML
authors.lastname: Kortelainen
authors.forename: Jussi T
authors.initials: JT
authors.lastname: Vuoristo
authors.forename: Heikki V
authors.initials: HV
authors.lastname: Huikuri
authors.forename: Katja S
authors.initials: KS
authors.lastname: Porvari
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002423:Cause of Death; D002467:Cell Nucleus / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007035:Hypothermia / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D017202:Myocardial Ischemia / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013312:Stress, Physiological; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494826:BAX protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1