Translational control of c-MYC by rapamycin promotes terminal myeloid differentiation.

Abstract:

:c-MYC inhibits differentiation and regulates the process by which cells acquire biomass, cell growth. Down-regulation of c-MYC, reduced cell growth, and decreased activity of the PI3K/AKT/mTORC1 signal transduction pathway are features of the terminal differentiation of committed myeloid precursors to polymorphonuclear neutrophils. Since mTORC1 regulates growth, we hypothesized that pharmacological inhibition of mTORC1 by rapamycin may reverse the phenotypic effects of c-MYC. Here we show that granulocytes blocked in their ability to differentiate by enforced expression of c-MYC can be induced to differentiate by reducing exogenous c-MYC expression through rapamycin treatment. Rapamycin also reduced expression of endogenous c-MYC and resulted in enhanced retinoid-induced differentiation. Total cellular c-Myc mRNA and c-MYC protein stability were unchanged by rapamycin, however the amount of c-Myc mRNA associated with polysomes was reduced. Therefore rapamycin limited expression of c-MYC by inhibiting c-Myc mRNA translation. These findings suggest that mTORC1 could be targeted to promote terminal differentiation in myeloid malignancies characterized by dysregulated expression of c-MYC.

journal_name

Blood

journal_title

Blood

authors

Wall M,Poortinga G,Hannan KM,Pearson RB,Hannan RD,McArthur GA

doi

10.1182/blood-2007-09-111856

subject

Has Abstract

pub_date

2008-09-15 00:00:00

pages

2305-17

issue

6

eissn

0006-4971

issn

1528-0020

pii

blood-2007-09-111856

journal_volume

112

pub_type

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