Activation of the p70 S6 kinase by all-trans-retinoic acid in acute promyelocytic leukemia cells

Lakhvir Lal, Yongzhong Li, Jessica Smith, Antonella Sassano, Shahab Uddin, Simrit Parmar, Martin S. Tallman, Saverio Minucci, Nissim Hay, Leonidas C. Platanias

Research output: Contribution to journalArticlepeer-review

Abstract

Although the mechanisms by which all-trans-retinoic acid (RA) regulates gene transcription are well understood, very little is known on the signaling events regulating RA-dependent initiation of mRNA translation. We examined whether the mammalian target of rapamycin (mTOR)/p70 S6 kinase pathway is activated by RA. RA treatment of sensitive cell lines resulted in phosphorylation/activation of mTOR and downstream induction of p70 S6 kinase activity. Such phosphorylation/activation of p70 S6 kinase was inducible in primary acute promyelocytic leukemia (APL) blasts and RA-sensitive NB-4 cells, but was defective in an NB-4 variant cell line (NB-4.007/6) that is resistant to the biologic effects of RA. The RA-dependent activation of p70 S5 kinase was also phosphatidylinositol 3′ kinase (P13′K)-dependent, and resulted in downstream phosphorylation of the S6 ribosomal protein on Ser235/236 and Ser240/244, events important for initiation of translation for mRNAs with oligopyrimidine tracts in their 5′ untranslated region. RA treatment of leukemia cells also resulted in an mTOR-mediated phosphorylation of the 4E-BP1 repressor of mRNA translation, to induce its deactivation and dissociation from the eukaryotic initiation factor-4E (elF-4E) complex. Altogether, these findings provide evidence for the existence of a novel RA-activated cellular pathway that regulates cap-dependent translation, and strongly suggest that this cascade plays a role in the Induction of retinold responses in APL cells.

Original languageEnglish
Pages (from-to)1669-1677
Number of pages9
JournalBlood
Volume105
Issue number4
DOIs
Publication statusPublished - Feb 15 2005

ASJC Scopus subject areas

  • Hematology

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