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Down-regulation of Myc is essential for terminal erythroid maturation

Jayapal, Senthil Raja ; Lee, Kian Leong ; Ji, Peng ; Kaldis, Philipp LU ; Lim, Bing and Lodish, Harvey F. (2010) In Journal of Biological Chemistry 285(51). p.40252-40265
Abstract

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.... (More)

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.

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author
publishing date
type
Contribution to journal
publication status
published
in
Journal of Biological Chemistry
volume
285
issue
51
pages
40252 - 40265
publisher
ASBMB
external identifiers
  • scopus:78650053515
  • pmid:20940306
ISSN
0021-9258
DOI
10.1074/jbc.M110.181073
language
English
LU publication?
no
id
5ab8f8be-997c-4397-8906-3cdf92c0bce8
date added to LUP
2019-09-18 14:05:49
date last changed
2020-01-13 02:23:47
@article{5ab8f8be-997c-4397-8906-3cdf92c0bce8,
  abstract     = {<p>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 G<sub>1</sub> 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 G<sub>1</sub>-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.</p>},
  author       = {Jayapal, Senthil Raja and Lee, Kian Leong and Ji, Peng and Kaldis, Philipp and Lim, Bing and Lodish, Harvey F.},
  issn         = {0021-9258},
  language     = {eng},
  month        = {12},
  number       = {51},
  pages        = {40252--40265},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Down-regulation of Myc is essential for terminal erythroid maturation},
  url          = {http://dx.doi.org/10.1074/jbc.M110.181073},
  doi          = {10.1074/jbc.M110.181073},
  volume       = {285},
  year         = {2010},
}