Down-regulation of Myc is essential for terminal erythroid maturation

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Down-regulation of Myc is essential for terminal erythroid maturation. / Jayapal, Senthil Raja; Lee, Kian Leong; Ji, Peng; Kaldis, Philipp; Lim, Bing; Lodish, Harvey F.

In: Journal of Biological Chemistry, Vol. 285, No. 51, 17.12.2010, p. 40252-40265.

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Jayapal, Senthil Raja ; Lee, Kian Leong ; Ji, Peng ; Kaldis, Philipp ; Lim, Bing ; Lodish, Harvey F. / Down-regulation of Myc is essential for terminal erythroid maturation. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 51. pp. 40252-40265.

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TY - JOUR

T1 - Down-regulation of Myc is essential for terminal erythroid maturation

AU - Jayapal, Senthil Raja

AU - Lee, Kian Leong

AU - Ji, Peng

AU - Kaldis, Philipp

AU - Lim, Bing

AU - Lodish, Harvey F.

PY - 2010/12/17

Y1 - 2010/12/17

N2 - Terminal differentiation of mammalian erythroid progenitors involves 4-5 cell divisions and induction of many erythroid important genes followed by chromatin and nuclear condensation and enucleation. The protein levels of c-Myc (Myc) are reduced dramatically during late stage erythroid maturation, coinciding with cell cycle arrest in G1 phase and enucleation, suggesting possible roles for c-Myc in either or both of these processes. Here we demonstrate that ectopic Myc expression affects terminal erythroid maturation in a dose-dependent manner. Expression of Myc at physiological levels did not affect erythroid differentiation or cell cycle shutdown but specifically blocked erythroid nuclear condensation and enucleation. Continued Myc expression prevented deacetylation of several lysine residues in histones H3 and H4 that are normally deacetylated during erythroid maturation. The histone acetyltransferase Gcn5 was up-regulated by Myc, and ectopic Gcn5 expression partially blocked enucleation and inhibited the late stage erythroid nuclear condensation and histone deacetylation. When overexpressed at levels higher than the physiological range, Myc blocked erythroid differentiation, and the cells continued to proliferate in cytokine-free, serum-containing culture medium with an early erythroblast morphology. Gene expression analysis demonstrated the dysregulation of erythropoietin signaling pathway and the up-regulation of several positive regulators of G1-S cell cycle checkpoint by supraphysiological levels of Myc. These results reveal an important dose-dependent function of Myc in regulating terminal maturation in mammalian erythroid cells.

AB - Terminal differentiation of mammalian erythroid progenitors involves 4-5 cell divisions and induction of many erythroid important genes followed by chromatin and nuclear condensation and enucleation. The protein levels of c-Myc (Myc) are reduced dramatically during late stage erythroid maturation, coinciding with cell cycle arrest in G1 phase and enucleation, suggesting possible roles for c-Myc in either or both of these processes. Here we demonstrate that ectopic Myc expression affects terminal erythroid maturation in a dose-dependent manner. Expression of Myc at physiological levels did not affect erythroid differentiation or cell cycle shutdown but specifically blocked erythroid nuclear condensation and enucleation. Continued Myc expression prevented deacetylation of several lysine residues in histones H3 and H4 that are normally deacetylated during erythroid maturation. The histone acetyltransferase Gcn5 was up-regulated by Myc, and ectopic Gcn5 expression partially blocked enucleation and inhibited the late stage erythroid nuclear condensation and histone deacetylation. When overexpressed at levels higher than the physiological range, Myc blocked erythroid differentiation, and the cells continued to proliferate in cytokine-free, serum-containing culture medium with an early erythroblast morphology. Gene expression analysis demonstrated the dysregulation of erythropoietin signaling pathway and the up-regulation of several positive regulators of G1-S cell cycle checkpoint by supraphysiological levels of Myc. These results reveal an important dose-dependent function of Myc in regulating terminal maturation in mammalian erythroid cells.

U2 - 10.1074/jbc.M110.181073

DO - 10.1074/jbc.M110.181073

M3 - Article

C2 - 20940306

AN - SCOPUS:78650053515

VL - 285

SP - 40252

EP - 40265

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

IS - 51

ER -