Retinoic Acid Promotes Apoptosis and Differentiation in Photoreceptors by Activating the P38 MAP Kinase Pathway

Genaro, Pablo De; Simón, M. Victoria; Rotstein, Nora P.; Politi, Luis E.

doi:10.1167/iovs.12-11049

Cited by 20 publications

(13 citation statements)

References 66 publications

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“…However, promoter analysis suggest that there is no typical retinoic acid response elements (RARE) located in the proximal promoter of Ape/Ref-1. It has been reported that noncanonical actions of ATRA including the activation of mitogen-activated protein kinase (MAPK) pathways in a variety of cancer cells [29], [30]. In this study, we found that ATRA treatment activated p38 and MSK (mitogen- and stress-activated protein kinase) kinases in a dose-dependent fashion ( Fig.…”

Section: Resultssupporting

confidence: 53%

Induction of Chemoresistance by All-Trans Retinoic Acid via a Noncanonical Signaling in Multiple Myeloma Cells

Liu

Jiang

et al. 2014

PLoS ONE

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Despite the successful application of all-trans retinoic acid (ATRA) in multiple myeloma treatment, ATRA-induced chemoresistance in the myeloma patients is very common in clinic. In this study, we evaluated the effect of ATRA on the expression of apurinic endonuclease/redox factor-1 (Ape/Ref-1) in the U266 and RPMI-8226 myeloma cells to explore the chemoresistance mechanism involved. ATRA treatment induced upregulation of Ape/Ref-1 via a noncanonical signaling pathway, leading to enhanced pro-survival activity counteracting melphalan (an alkylating agent). ATRA rapidly activated p38-MSK (mitogen- and stress activated protein kinase) cascade to phosphorylate cAMP response element-binding protein (CREB). Phosphorylated CREB was recruited to the Ape/Ref-1 promoter to evoke the gene expression. The stimulation of ATRA on Ape/Ref-1 expression was attenuated by either p38-MSK inhibitors or overexpression of dominant-negative MSK1 mutants. Moreover, ATRA-mediated Ape/Ref-1 upregulation was correlated with histone modification and activation of CBP/p300, an important cofactors for CREB transcriptional activity. C646, a competitive CBP/p300 inhibitor, abolished the upregulation of Ape/Ref-1 induced by ATRA. Intriguingly, CBP rather than p300 played a dominant role in the expression of Ape/Ref-1. Hence, our study suggests the existence of a noncanonical mechanism involving p38-MSK-CREB cascade and CBP induction to mediate ATRA-induced Ape/Ref-1 expression and acquired chemoresistance in myeloma cells.

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Section: Resultssupporting

confidence: 53%

Induction of Chemoresistance by All-Trans Retinoic Acid via a Noncanonical Signaling in Multiple Myeloma Cells

Liu

Jiang

et al. 2014

PLoS ONE

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“…Excess ROS generation and AA release play essential roles in the initiation of apoptosis in platelets. 21, 39 As p38/cPLA 2 is involved in the regulation of nucleated cell apoptosis 40, 41, 42, 43 and the possible involvement of p38/cPLA 2 in the induction of platelet apoptotic events is not known, we compared the mechanism of p38/cPLA 2 -mediated signaling induced by platelet agonists and ABT-737.…”

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confidence: 99%

Dual role of the p38 MAPK/cPLA 2 pathway in the regulation of platelet apoptosis induced by ABT-737 and strong platelet agonists

et al. 2013

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p38 Mitogen-activated protein (MAP) kinase is involved in the apoptosis of nucleated cells. Although platelets are anucleated cells, apoptotic proteins have been shown to regulate platelet lifespan. However, the involvement of p38 MAP kinase in platelet apoptosis is not yet clearly defined. Therefore, we investigated the role of p38 MAP kinase in apoptosis induced by a mimetic of BH3-only proteins, ABT-737, and in apoptosis-like events induced by such strong platelet agonists as thrombin in combination with convulxin (Thr/Cvx), both of which result in p38 MAP kinase phosphorylation and activation. A p38 inhibitor (SB202190) inhibited the apoptotic events induced by ABT-737 but did not influence those induced by Thr/Cvx. The inhibitor also reduced the phosphorylation of cytosolic phospholipase A2 (cPLA2), an established p38 substrate, induced by ABT-737 or Thr/Cvx. ABT-737, but not Thr/Cvx, induced the caspase 3-dependent cleavage and inactivation of cPLA2. Thus, p38 MAPK promotes ABT-737-induced apoptosis by inhibiting the cPLA2/arachidonate pathway. We also show that arachidonic acid (AA) itself and in combination with Thr/Cvx or ABT-737 at low concentrations prevented apoptotic events, whereas at high concentrations it enhanced such events. Our data support the hypothesis that the p38 MAPK-triggered arachidonate pathway serves as a defense mechanism against apoptosis under physiological conditions.

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“…Significantly fewer cells were seen to undergo PCD between E9 and E14 after RARB knockdown, arguing against a sensitizing effect of RA signaling in the CG, at least via RARβ. However, another recent study revealed that in retinal neuron cultures, RA selectively increases apoptosis in photoreceptors, when applied while cells still proliferated; regardless of the developmental stage although, RA promoted photoreceptor differentiation, shown by the expression of opsins and neurite outgrowth (De Genaro et al, ).…”

Section: Discussionmentioning

confidence: 99%

RARβ regulates neuronal cell death and differentiation in the avian ciliary ganglion

Koszinowski

Boerries

Busch

et al. 2015

Developmental Neurobiology

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Programmed cell death during chicken ciliary ganglion (CG) development is mostly discussed as an extrinsically regulated process, guided either by the establishment of a functional balance between preganglionic and postganglionic activity or the availability of target‐derived neurotrophic factors. We found that the expression of the gene coding for the nuclear retinoic acid receptor β (RARB) is transiently upregulated prior to and during the execution phase of cell death in the CG. Using retroviral vectors, the expression of RARB was knocked down during embryonic development in ovo. The knockdown led to a significant increase in CG neuron number after the cell death phase. BrdU injections and active caspase‐3 staining revealed that this increase in neuron number was due to an inhibition of apoptosis during the normal cell death phase. Furthermore, apoptotic neuron numbers were significantly increased at a stage when cell death is normally completed. While the cholinergic phenotype of the neurons remained unchanged after RARB knockdown, the expression of the proneural gene Cash1 was increased, but somatostatin‐like immunoreactivity, a hallmark of the mature choroid neuron population, was decreased. Taken together, these results point toward a delay in neuronal differentiation as well as cell death. The availability of nuclear retinoic acid receptor β (RARβ) and RARβ‐induced transcription of genes could therefore be a new intrinsic cue for the maturation of CG neurons and their predisposition to undergo cell death. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 1204–1218, 2015

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Retinoic Acid Promotes Apoptosis and Differentiation in Photoreceptors by Activating the P38 MAP Kinase Pathway

Cited by 20 publications

References 66 publications

Induction of Chemoresistance by All-Trans Retinoic Acid via a Noncanonical Signaling in Multiple Myeloma Cells

Induction of Chemoresistance by All-Trans Retinoic Acid via a Noncanonical Signaling in Multiple Myeloma Cells

Dual role of the p38 MAPK/cPLA 2 pathway in the regulation of platelet apoptosis induced by ABT-737 and strong platelet agonists

RARβ regulates neuronal cell death and differentiation in the avian ciliary ganglion

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