Bcl2, a transcriptional target of p38α, is critical for neuronal commitment of mouse embryonic stem cells

Trouillas, Marina; Saucourt, Claire; Duval, David Timothy; Gauthereau, Xavier; Thibault, Christelle; Dembélé, Doulaye; Féraud, Olivier; Ménager, Jean; Rallu, Muriel; Pradier, Laurent; Bœuf, Hélène

doi:10.1038/cdd.2008.63

Cited by 33 publications

(26 citation statements)

References 49 publications

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“…Apart from its role in mediating proper Nanog, Klf4, and Tbx3 expression in undifferentiated cells, Satb1 may also function in the process of ES cell differentiation by regulating the expression of Bcl2, which is required for neural commitment of ES cells (Trouillas et al 2008). BCL2 is a SATB1 target in human cells (Ramakrishnan et al 2000) and, in agreement with this observation, we found that Bcl2 is also a Satb1 target in murine ES cells.…”

Section: Satb2supporting

confidence: 77%

Satb1 and Satb2 regulate embryonic stem cell differentiation and Nanog expression

Savarese

Dávila²,

Nechanitzky³

et al. 2009

Genes Dev.

128

148

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Satb1 and the closely related Satb2 proteins regulate gene expression and higher-order chromatin structure of multigene clusters in vivo. In examining the role of Satb proteins in murine embryonic stem (ES) cells, we find that Satb1−/− cells display an impaired differentiation potential and augmented expression of the pluripotency determinants Nanog, Klf4, and Tbx3. Metastable states of self-renewal and differentiation competence have been attributed to heterogeneity of ES cells in the expression of Nanog. Satb1−/− cultures have a higher proportion of Nanoghigh cells, and an increased potential to reprogram human B lymphocytes in cell fusion experiments. Moreover, Satb1-deficient ES cells show an increased expression of Satb2, and we find that forced Satb2 expression in wild-type ES cells antagonizes differentiation-associated silencing of Nanog and enhances the induction of NANOG in cell fusions with human B lymphocytes. An antagonistic function of Satb1 and Satb2 is also supported by the almost normal differentiation potential of Satb1−/−Satb2−/− ES cells. Taken together with the finding that both Satb1 and Satb2 bind the Nanog locus in vivo, our data suggest that the balance of Satb1 and Satb2 contributes to the plasticity of Nanog expression and ES cell pluripotency.

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Section: Satb2supporting

confidence: 77%

Satb1 and Satb2 regulate embryonic stem cell differentiation and Nanog expression

Savarese

Dávila²,

Nechanitzky³

et al. 2009

Genes Dev.

128

148

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“…In the functional studies, pharmacological inhibitors PD169316 and SB203580 are frequently used as p38 MAPK inhibitor. [44][45][46] In the present study, although PD169316 and SB203580 inhibit the phosphorylation of p38 MAPK and the downstream target ATF-2, these two inhibitors exert an opposing effect in PDT-treated HK-1 cells. The discrepancy in the action between PD169316 (anti-apoptotic) and SB203580 (apoptosis enhancing) in PDT-treated HK-1 cells is unknown.…”

Section: Discussionmentioning

confidence: 72%

Role of mitogen‐activated protein kinase in Zn‐BC‐AM PDT‐induced apoptosis in nasopharyngeal carcinoma cells

Koon

Chan

et al. 2010

Cell Biochemistry & Function

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Photodynamic therapy (PDT) with a recently developed photosensitizer Zn-BC-AM was found to effectively induce apoptosis in a well-differentiated nasopharyngeal carcinoma (NPC) HK-1 cell line. Sustained activation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK) as well as a transient increase in activation of extracellular signal-regulated kinase (ERK) were observed immediately after Zn-BC-AM PDT. A commonly used p38 MAPK/JNK pharmacological inhibitor PD169316 was found to reduce PDT-induced apoptosis of HK-1 cells. PD169316 also prevented the loss of Bcl-2 and Bcl-xL in PDT-treated HK-1 cells. However, inhibition of JNK with SP600125 had no effect on Zn-BC-AM PDT-induced apoptosis while inhibition of ERK with PD98059 or p38 MAPK with SB203580 significantly increased Zn-BC-AM PDT-induced apoptosis. Further study showed that knockdown of the p38beta isoform with siRNA also increased Zn-BC-AM PDT-induced apoptosis, indicating that the anti-apoptotic effect of PD169316 in PDT-treated HK-1 cells was probably independent of p38 MAPK or JNK activation. Taken together, the results suggest that inhibition of p38beta and ERK may enhance the therapeutic efficacy of Zn-BC-AM PDT on NPC cells. It should be noted that data only based on the use of PD169316 should be interpreted in caution.

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“…Because the main research focus around the Bcl-2 family of proteins is related to apoptosis regulation, other mechanisms by which these proteins could modulate cellular commitment and differentiation have remained elusive and controversial but are becoming steady and firmly established (19,45,48,49). A conservative view would be that of Boeuf et al (41,50,51), who underlined that the cell commitment modulation exerted by Bcl-2 proteins was closely related to their survival function, through the regulation of the mitogen-activated protein kinase pathway. In our model, Bcl-X L displayed an important antiapoptotic role in differentiating cells, but this is insufficient to explain the observed effects and needs to be considered in combination with the induction of neurogenesis (see the model in Fig.…”

Section: Discussionmentioning

confidence: 94%

“…We demonstrate here that Bcl-X L protected hVM1 NSCs from apoptosis during differentiation and in response to cytotoxic insults. Apoptotic cell death in differentiating hVM1-ø cells was generalized (not DAn-specific) and started at early differentiation time points (such as in mouse and human embryonic stem cells and throughout brain development) (21,40,41). Mechanistic stud- ies revealed that caspase activation and mitochondria (by the release of apoptosis-inducing factor, caspase-9 activation, and loss of ⌬⌿ mit ) were directly involved in this process.…”

Section: Discussionmentioning

confidence: 99%

“…Bcl-2 and Bax (Bcl-2-associated X protein) were also shown to induce the commitment of progenitor cells (41,47). Because the main research focus around the Bcl-2 family of proteins is related to apoptosis regulation, other mechanisms by which these proteins could modulate cellular commitment and differentiation have remained elusive and controversial but are becoming steady and firmly established (19,45,48,49).…”

Section: Discussionmentioning

confidence: 99%

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In Vitro and in Vivo Enhanced Generation of Human A9 Dopamine Neurons from Neural Stem Cells by Bcl-XL

Courtois

Castillo

Seiz

et al. 2010

Journal of Biological Chemistry

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Parkinson disease (PD)2 motor symptoms arise from the progressive degeneration of dopaminergic neurons (DAn). Experimental therapies, based on the cell replacement of the lost substantia nigra pars compacta (SNpc) DAn using human ventral mesencephalic (VM) fetal tissue provided proof of principle of a therapeutic effect of the transplants on a long term basis (1). However, in addition to ethical problems related to fetal tissue procurement, practical limitations were found, like the need for large amounts of VM tissue and the elevated cell death rate of the transplanted cells (2).As an alternative, human neural stem cells (hNSCs) derived from the developing and adult central nervous system were initially used, but they were inefficient for DAn generation (3). Another stem cell source, the embryonic stem cells, required long and difficult differentiation protocols as well as neuronal and DAn progenitor selection to obtain high amounts of DAn (4, 5). Previous transplantation studies established that the generation of functional SNpc DAn in vivo was highly dependent on the regional tissue origin, the VM being the optimal region (6), and that only DAn with SNpc properties (meaning adequate patterning, transcription factor, and differentiated protein profile) were able to reinervate the striatum and induce a therapeutic effect (7). Therefore, human fetal VM-derived cell strains were established (8, 9), but their use was hindered by a limited and unstable DA differentiation potential (10) (as it was previously described for rodent and human VM neurospheres (11, 12)) and DA-related oxidative stress (13).To the human cell lines of VM origin previously reported (8, 14), we have recently contributed a new immortalized human fetal VM NSC line (hVM1), which shows a great potential for the generation of SNpc DAn in vitro (15). In the present work, we have aimed at increasing our understanding of key factors involved in phenotypical stability, DAn generation, and functional maturation both in vitro and in vivo.

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Bcl2, a transcriptional target of p38α, is critical for neuronal commitment of mouse embryonic stem cells

Cited by 33 publications

References 49 publications

Satb1 and Satb2 regulate embryonic stem cell differentiation and Nanog expression

Satb1 and Satb2 regulate embryonic stem cell differentiation and Nanog expression

Role of mitogen‐activated protein kinase in Zn‐BC‐AM PDT‐induced apoptosis in nasopharyngeal carcinoma cells

In Vitro and in Vivo Enhanced Generation of Human A9 Dopamine Neurons from Neural Stem Cells by Bcl-XL

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