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

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 S6 kinase was also phosphatidylinositol 3' kinase (PI3'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 (eIF-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 retinoid responses in APL cells.

• Authors: Lakhvir Lal, Yongzhong Li, Jessica Smith, Antonella Sassano, Shahab Uddin, Simrit Parmar, Martin S Tallman, Saverio Minucci, Nissim Hay, Leonidas C Platanias
• Journal: Blood (Blood) Vol. 105 Issue 4 Pg. 1669-77 (Feb 15 2005) ISSN: 0006-4971 [Print] United States
• PMID: 15471950 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Eukaryotic Initiation Factor-4E
• Growth Inhibitors
• RNA Caps
• Serine
• Tretinoin
• Protein Kinases
• MTOR protein, human
• Ribosomal Protein S6 Kinases, 70-kDa
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Cell Differentiation (physiology)
• Cell Line, Tumor
• Enzyme Activation
• Eukaryotic Initiation Factor-4E (metabolism)
• Growth Inhibitors (pharmacology)
• Humans
• Leukemia, Promyelocytic, Acute (enzymology, metabolism, pathology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Protein Kinases (metabolism, physiology)
• RNA Caps (metabolism)
• Ribosomal Protein S6 Kinases, 70-kDa (metabolism, physiology)
• Serine (metabolism)
• Signal Transduction (physiology)
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases
• Tretinoin (pharmacology)