Role of the translational repressor 4E-BP1 in the regulation of p21Waf1/Cip1 expression by retinoids

Kannan-Thulasiraman, Padma; Dolniak, Blazej; Kaur, Surinder; Sassano, Antonella; Kalvakolanu, Dhananjaya V.; Hay, Nissim; Platanias, Leonidas C.

doi:10.1016/j.bbrc.2008.02.028

Cited by 9 publications

(4 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, p27 and p53 protein accumulations following proteasome inhibition were not modified by the loss of p70S6K. Given the fact that these latter proteins contain an IRES element, contrarily to p21 (Miskimins et al, ; Ray et al, ; Kannan‐Thulasiraman et al, ), we hypothesize that p70S6K could be only required to enhance cap‐dependent translation of proteins but further studies will be required to explore this assumption. Moreover, we suggest that in the mTOR/S6K pathway, the kinase p70S6K played a major role in the control of p21 translation as we showed that mTOR inhibition did not suppress p21 induction upon MEK activation contrarily to p70S6K targeting.…”

Section: Discussionmentioning

confidence: 87%

MEK1/2 Overactivation Can Promote Growth Arrest by Mediating ERK1/2-Dependent Phosphorylation of p70S6K

et al. 2014

View full text Add to dashboard Cite

The extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein (MAP) kinase pathway has been involved in the positive and negative regulation of cell proliferation. Upon mitogen stimulation, ERK1/ERK2 activation is necessary for G1- to S-phase progression whereas when hyperactived, this pathway could elicit cell cycle arrest. The mechanisms involved are not fully elucidated but a kinase-independent function of ERK1/2 has been evidenced in the MAPK-induced growth arrest. Here, we show that p70S6K, a central regulator of protein biosynthesis, is essential for the cell cycle arrest induced by overactivation of ERK1/2. Indeed, whereas MEK1 silencing inhibits cell cycle progression, we demonstrate that active mutant form of MEK1 or MEK2 triggers a G1 phase arrest by stimulating an activation of p70S6K by ERK1/2 kinases. Silencing of ERK1/2 activity by shRNA efficiently suppresses p70S6K phosphorylation on Thr421/Ser424 and S6 phosphorylation on Ser240/244 as well as p21 expression, but these effects can be partially reversed by the expression of kinase-dead mutant form of ERK1 or ERK2. In addition, we demonstrate that the kinase p70S6K modulates neither the p21 gene transcription nor the stability of the protein but enhances the translation of the p21 mRNA. In conclusion, our data emphasizes the importance of the translational regulation of p21 by the MEK1/2-ERK1/2-p70S6K pathway to negatively control the cell cycle progression.

show abstract

Section: Discussionmentioning

confidence: 87%

MEK1/2 Overactivation Can Promote Growth Arrest by Mediating ERK1/2-Dependent Phosphorylation of p70S6K

et al. 2014

View full text Add to dashboard Cite

show abstract

“…This raises the intriguing possibility that loss of 4E-BP1 mediates escape from this proliferative arrest despite increased levels of p53, arguing that disco-induced ACS is more influenced by 4E-BP1 than by p53. Previous studies have shown that 4E-BP1 can modulate expression of p21 and HDM2 independently of p53 transcriptional regulation (29,30). An alternative explanation to rationalize the survival of AD32 cells with high expression of p53 may be that p53 acts as a repressor of senescence, as has been recently proposed in a p21-driven model system (31).…”

Section: Discussionmentioning

confidence: 98%

Resistance to discodermolide, a microtubule-stabilizing agent and senescence inducer, is 4E-BP1–dependent

Chao

Lin

Brouwer‐Visser

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Discodermolide is a microtubule-stabilizing agent that induces accelerated cell senescence. A discodermolide-resistant cell line, AD32, was generated from the human lung cancer cell line A549. We hypothesize that the major resistance mechanism in these cells is escape from accelerated senescence. AD32 cells have decreased levels of 4E-BP1 mRNA and protein, relative to the parental discodermolide-sensitive A549 cells. Lentiviral-mediated re-expression of wild-type 4E-BP1 in AD32 cells increased the proliferation rate and reverted resistance to discodermolide via restoration of discodermolide-induced accelerated senescence. Consistent with this, cell growth and response to discodermolide was confirmed in vivo using tumor xenograft models. Furthermore, reintroduction of a nonphosphorylatable mutant (Thr-37/46 Ala) of 4E-BP1 was able to partially restore sensitivity and enhance proliferation in AD32 cells, suggesting that these effects are independent of phosphorylation by mTORC1. Microarray profiling of AD32-resistant cells versus sensitive A549 cells, and subsequent unbiased gene ontology analysis, identified molecular pathways and functional groupings of differentially expressed mRNAs implicated in overcoming discodermolide-induced senescence. The most statistically significant classes of differentially expressed genes included p53 signaling, G2/M checkpoint regulation, and genes involved in the role of BRCA1 in the DNA damage response. Consistent with this, p53 protein expression was up-regulated and had increased nuclear localization in AD32 cells relative to parental A549 cells. Furthermore, the stability of p53 was enhanced in AD32 cells. Our studies propose a role for 4E-BP1 as a regulator of discodermolide-induced accelerated senescence. drug resistance | senescence reversion | TOR signaling

show abstract

“…In the RA/IFN-induced differentiation model of AML cells in which RIG-I cDNA was originally identified, an initial and transient AKT-mTOR activation probably facilitates the full induction of ISG proteins (including RIG-I itself) that serve as the key effectors to RA/IFN signaling (Kaur et al, 2008). However, a persistent AKT-mTOR activation will preclude the realization of the growth inhibition and differentiation induction (Gery et al, 2007;Kannan-Thulasiraman et al, 2008), or even the degradation of oncogenic protein via autophagy activation (Isakson et al, 2010). Therefore, AKT-mTOR activation has to be limited once the accumulation of ISGs is achived.…”

Section: Discussionmentioning

confidence: 99%

RIG-I Modulates Src-Mediated AKT Activation to Restrain Leukemic Stemness

Jiang

Chen

et al. 2014

Molecular Cell

View full text Add to dashboard Cite

Retinoic acid (RA)-inducible gene I (RIG-I) is highly upregulated and functionally implicated in the RA-induced maturation of acute myeloid leukemia (AML) blasts. However, the underlying mechanism and the biological relevance of RIG-I expression to the maintenance of leukemogenic potential are poorly understood. Here, we show that RIG-I, without priming by foreign RNA, inhibits the Src-facilitated activation of AKT-mTOR in AML cells. Moreover, in a group of primary human AML blasts, RIG-I reduction renders the Src family kinases hyperactive in promoting AKT activation. Mechanistically, a PxxP motif in RIG-I, upon the N-terminal CARDs' association with the Src SH1 domain, competes with the AKT PxxP motif for recognizing the Src SH3 domain. In accordance, mutating PxxP motif prevents Rig-I from inhibiting AKT activation, cytokine-stimulated myeloid progenitor proliferation, and in vivo repopulating capacity of leukemia cells. Collectively, our data suggest an antileukemia activity of RIG-I via competitively inhibiting Src/AKT association.

show abstract

Role of the translational repressor 4E-BP1 in the regulation of p21Waf1/Cip1 expression by retinoids

Cited by 9 publications

References 46 publications

MEK1/2 Overactivation Can Promote Growth Arrest by Mediating ERK1/2-Dependent Phosphorylation of p70S6K

MEK1/2 Overactivation Can Promote Growth Arrest by Mediating ERK1/2-Dependent Phosphorylation of p70S6K

Resistance to discodermolide, a microtubule-stabilizing agent and senescence inducer, is 4E-BP1–dependent

RIG-I Modulates Src-Mediated AKT Activation to Restrain Leukemic Stemness

Contact Info

Product

Resources

About