Activation of the p70 S6 kinase by all-trans-retinoic acid in acute promyelocytic leukemia cells.
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.
Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, IL 60611, USA.
Lakhvir
L
Lal
Yongzhong
Y
Li
Jessica
J
Smith
Antonella
A
Sassano
Shahab
S
Uddin
Simrit
S
Parmar
Martin S
MS
Tallman
Saverio
S
Minucci
Nissim
N
Hay
Leonidas C
LC
Platanias
D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology; D012315:RNA Caps / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism* / Q000502:physiology; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014212:Tretinoin / Q000494:pharmacology*
D039561:Eukaryotic Initiation Factor-4E; D006131:Growth Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D012315:RNA Caps; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D012694:Serine; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014212:Tretinoin; C546842:MTOR protein, human