title: Calpeptin increases the activity of upstream stimulatory factor and induces high level globin gene expression in erythroid cells.
abstract: Differentiation of erythroid cells is regulated by cell signaling pathways including those that change the intracellular concentration of calcium. Calcium-dependent proteases have been shown previously to process and regulate the activity of specific transcription factors. We show here that the protein levels of upstream stimulatory factor (USF) increase during differentiation of murine erythroleukemia (MEL) cells. USF was subject to degradation by the Ca(2+)-dependent protease m-calpain in undifferentiated but not in differentiated MEL cells. Treatment of MEL cells with the specific calpain inhibitor calpeptin increased the levels of USF and strongly induced expression of the adult alpha- and beta-globin genes. The induction of globin gene expression was associated with an increase in the association of USF and RNA po ly mer ase II with regulatory elements of the beta-globin gene locus. Calpeptin also induced high level alpha- and beta-globin gene expression in primary CD71-positive erythroid progenitor cells. The combined data suggest that inhibition of calpain activity is required for erythroid differentiation-associated increase in globin gene expression.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: I-Ju
authors.initials: IJ
authors.lastname: Lin
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhou
authors.forename: Valerie J
authors.initials: VJ
authors.lastname: Crusselle-Davis
authors.forename: Babak
authors.initials: B
authors.lastname: Moghimi
authors.forename: Kunjal
authors.initials: K
authors.lastname: Gandhi
authors.forename: Archana
authors.initials: A
authors.lastname: Anantharaman
authors.forename: Dorjan
authors.initials: D
authors.lastname: Pantic
authors.forename: Suming
authors.initials: S
authors.lastname: Huang
authors.forename: Giridhararao
authors.initials: G
authors.lastname: Jayandharan
authors.forename: Li
authors.initials: L
authors.lastname: Zhong
authors.forename: Arun
authors.initials: A
authors.lastname: Srivastava
authors.forename: Jörg
authors.initials: J
authors.lastname: Bungert
mesh_terms: D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D002454:Cell Differentiation; D004151:Dipeptides / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D041905:Erythroid Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005914:Globins / Q000235:genetics* / Q000378:metabolism; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051189:Murinae; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D051720:Upstream Stimulatory Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004151:Dipeptides; D004791:Enzyme Inhibitors; D051720:Upstream Stimulatory Factors; C071482:calpeptin; D005914:Globins; D012319:RNA Polymerase II; D002154:Calpain; C449000:m-calpain