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 language | English |
|---|---|
| Pages (from-to) | 1669-1677 |
| Number of pages | 9 |
| Journal | Blood |
| Volume | 105 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Feb 15 2005 |
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ASJC Scopus subject areas
- Hematology
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Activation of the p70 S6 kinase by all-trans-retinoic acid in acute promyelocytic leukemia cells. / Lal, Lakhvir; Li, Yongzhong; Smith, Jessica; Sassano, Antonella; Uddin, Shahab; Parmar, Simrit; Tallman, Martin S.; Minucci, Saverio; Hay, Nissim; Platanias, Leonidas C.
In: Blood, Vol. 105, No. 4, 15.02.2005, p. 1669-1677.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Activation of the p70 S6 kinase by all-trans-retinoic acid in acute promyelocytic leukemia cells
AU - Lal, Lakhvir
AU - Li, Yongzhong
AU - Smith, Jessica
AU - Sassano, Antonella
AU - Uddin, Shahab
AU - Parmar, Simrit
AU - Tallman, Martin S.
AU - Minucci, Saverio
AU - Hay, Nissim
AU - Platanias, Leonidas C.
PY - 2005/2/15
Y1 - 2005/2/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=13544274110&partnerID=8YFLogxK
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U2 - 10.1182/blood-2004-06-2078
DO - 10.1182/blood-2004-06-2078
M3 - Article
C2 - 15471950
AN - SCOPUS:13544274110
VL - 105
SP - 1669
EP - 1677
JO - Blood
JF - Blood
SN - 0006-4971
IS - 4
ER -