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Blood, 15 February 2005, Vol. 105, No. 4, pp. 1669-1677.
Prepublished online as a Blood First Edition Paper on October 7, 2004; DOI 10.1182/blood-2004-06-2078.
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Submitted June 7, 2004
Accepted September 30, 2004
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, and Leonidas C Platanias*
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University School of Medicine and Lakeside VA Medical Center, Chicago, IL, USA
Section of Hematology-Oncology, University of Chicago, Chicago, IL, USA
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA
* Corresponding author; email: l-platanias{at}northwestern.edu.
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 biological effects of RA. The RA-dependent activation of p70 S6 kinase was also PI3 kinase-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 de-activation 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.
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