p53 is involved in the differentiation but not in the differentiation-associated apoptosis of myoblasts

Cerone, Maria Antonietta; Marchetti, Alessandra; Bossi, Gianluca; Blandino, Giovanni; Sacchi, Ada; Soddu, Silvia

doi:10.1038/sj.cdd.4400676

Cited by 32 publications

(36 citation statements)

References 10 publications

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“…7F). This is consistent with previous reports employing dominant negative mutants of p53 as well as p53-/-cells which indicate that p53 is not involved in the apoptosis of skeletal myoblasts as a consequence of culture in DM [19].…”

Section: Resultssupporting

confidence: 94%

“…If they could not differentiate, one Since increased expression of PUMA was originally observed in response to activation of the transcription factor p53 [35][36][37], we used pifithrin, a selective pharmacological inhibitor of p53 [38], to examine a role for p53 in the induction of PUMA as a consequence of culture in DM. A role for p53 in the differentiation of skeletal myoblasts is well established [19,39] so we first assessed the effect of pifithrin on differentiation as monitored by the expression of myogenin. As predicted, pifithrin inhibited the expression of myogenin mRNA and protein as a consequence of culture in DM (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Despite the wealth of molecular knowledge detailing skeletal myoblast determination and differentiation, information regarding the molecular mechanisms controlling the apoptosis associated with skeletal myoblast differentiation is limited [3,4,[17][18][19][20][21][22][23][24]. The molecular mechanisms responsible for apoptosis in other systems, however, have been extensively studied.…”

Section: Introductionmentioning

confidence: 99%

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Increased expression of the pro-apoptotic Bcl2 family member PUMA is required for mitochondrial release of cytochrome C and the apoptosis associated with skeletal myoblast differentiation

et al. 2007

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We have previously shown that when skeletal myoblasts are cultured in differentiation medium (DM), roughly 30% undergo caspase 3-dependent apoptosis rather than differentiation. Herein, we investigate the molecular mechanism responsible for the activation of caspase 3 and the ensuing apoptosis. When 23A2 myoblasts are cultured in DM, caspase 9 activity is increased and pharmacological abrogation of caspase 9 activation impairs caspase 3 activation and apoptosis. Further, we detect a time dependent release of mitochondrial cytochrome C into the cytosol in roughly 30% of myoblasts. Inclusion of cycloheximide inhibits the release of cytochrome C, the activation of caspase 9 and apoptosis. These data indicate that the mitochondrial pathway plays a role in this apoptotic process and that engagement of this pathway relies on de novo protein synthesis. Through RT-PCR and immunoblot analysis, we have determined that the expression level of the pro-apoptotic Bcl2 family member PUMA is elevated when 23A2 myoblasts are cultured in DM. Further, silencing of PUMA inhibits the release of cytochrome C and apoptosis. Signaling by the transcription factor p53 is not responsible for the increased level of PUMA. Finally, myoblasts rescued from apoptosis by either inhibition of elevated caspase 9 activity or silencing of PUMA are competent for differentiation. These results indicate a critical role for PUMA in the apoptosis associated with skeletal myoblast differentiation and that a p53-independent mechanism is responsible for the increased expression of PUMA in these cells.

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Section: Resultssupporting

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Increased expression of the pro-apoptotic Bcl2 family member PUMA is required for mitochondrial release of cytochrome C and the apoptosis associated with skeletal myoblast differentiation

et al. 2007

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“…We found that both protein and activity levels of p53 increase during myogenesis, consistent with previous reports on the differentiation of mammalian muscle in culture (47,48). Although stabilization of p53 activity during the induction of myogenesis increases the overall efficiency of the process, inhibition of p53 prevents myotube formation, demonstrating that p53 is essential during muscle differentiation in salamander cells.…”

Section: Salamander δNp73 Acts As a P53 Dominant-negative And Its Modsupporting

confidence: 80%

Regulation of p53 is critical for vertebrate limb regeneration

Yun

Gates

Brockes

2013

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

109

101

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Extensive regeneration of the vertebrate body plan is found in salamander and fish species. In these organisms, regeneration takes place through reprogramming of differentiated cells, proliferation, and subsequent redifferentiation of adult tissues. Such plasticity is rarely found in adult mammalian tissues, and this has been proposed as the basis of their inability to regenerate complex structures. Despite their importance, the mechanisms underlying the regulation of the differentiated state during regeneration remain unclear. Here, we analyzed the role of the tumor-suppressor p53 during salamander limb regeneration. The activity of p53 initially decreases and then returns to baseline. Its down-regulation is required for formation of the blastema, and its upregulation is necessary for the redifferentiation phase. Importantly, we show that a decrease in the level of p53 activity is critical for cell cycle reentry of postmitotic, differentiated cells, whereas an increase is required for muscle differentiation. In addition, we have uncovered a potential mechanism for the regulation of p53 during limb regeneration, based on its competitive inhibition by ΔNp73. Our results suggest that the regulation of p53 activity is a pivotal mechanism that controls the plasticity of the differentiated state during regeneration. myogenesis | chondrogenesis | p73 | carcinogenesis U nlike mammals, which exhibit limited regenerative abilities, the urodele amphibians-or salamanders-are capable of regenerating an extraordinary range of body structures, including ocular tissues, tail, sections of the heart, parts of the nervous system, and entire limbs (1). In salamanders, such as the newt and axolotl, limb regeneration depends on the formation of a blastema, a mound of progenitor cells of restricted potential that arises after amputation (2-4). Following a period of proliferation, blastema cells redifferentiate and restore the structures of the limb.Extensive evidence indicates that limb regeneration depends on reprogramming of cells in mature limb tissues. Upon amputation, muscle, cartilage, and connective tissue cells underneath the injury site lose their differentiated characteristics and reenter the cell cycle to give rise to the blastema (5-8). This mechanism has also been observed during zebrafish heart and fin regeneration (9, 10). In contrast, reversals of the differentiated state are rarely observed in mammalian tissues, which led to the suggestion that inability to undergo dedifferentiation could contribute to the failure of regeneration in mammals (11). Despite their significance, the mechanisms underlying regulation of the differentiated state during vertebrate regeneration remain poorly understood.Recently, the tumor suppressor p53, whose best-characterized functions are in the maintenance of genome stability (12), has been implicated in the suppression of artificial cell reprogramming to pluripotency (13-17) and the promotion of differentiation pathways in mammals (18). In addition, it has been observed that inhibiting p...

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“…Thus, the capacity of MyoD to induce growth arrest (and differentiation) or apoptosis is reminiscent of p53 function in other cell types. Interestingly, in skeletal myoblasts, p53 plays crucial role in differentiation and not in apoptosis [10,29,30]. Nonetheless, the challenge mentioned above to understand the mechanism which allows MyoD to induce PUMA and apoptosis, rather than p21CDK, cell cycle exit and muscle specific genes (Fig.…”

Section: Discussionmentioning

confidence: 96%

Increased expression of the pro-apoptotic Bcl2 family member PUMA and apoptosis by the muscle regulatory transcription factor MyoD in response to a variety of stimuli

2009

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We have previously reported that the level of MyoD expression correlates with the level of apoptosis that occurs in a subpopulation of skeletal myoblasts induced to differentiate by serum withdrawal. Herein we document that MyoD expression contributes to the level of apoptosis in myoblasts and fibroblasts in response to a variety of apoptotic stimuli. Specifically, re-expression of MyoD in skeletal myoblasts rendered defective for both differentiation and apoptosis by the expression of oncogenic Ras restores their ability to undergo both differentiation and apoptosis in response to serum withdrawal. Further, using a fibroblast cell line expressing an estrogen receptor:MyoD fusion protein, we have determined that addition of estrogen sensitizes these fibroblasts to apoptosis induced by serum withdrawal, or by treatment with etoposide or thapsigargin. RNAi mediated silencing of MyoD in either 23A2 or C2C12 myoblasts renders these cells resistant to apoptosis induced by serum withdrawal, or by treatment with etoposide or thapsigargin. Finally, MyoD mediated regulation of the apoptotic response to these various stimuli, in both myoblasts and fibroblasts, correlates with the level of induction of the pro-apoptotic Bcl2 family member PUMA.

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p53 is involved in the differentiation but not in the differentiation-associated apoptosis of myoblasts

Cited by 32 publications

References 10 publications

Increased expression of the pro-apoptotic Bcl2 family member PUMA is required for mitochondrial release of cytochrome C and the apoptosis associated with skeletal myoblast differentiation

Increased expression of the pro-apoptotic Bcl2 family member PUMA is required for mitochondrial release of cytochrome C and the apoptosis associated with skeletal myoblast differentiation

Regulation of p53 is critical for vertebrate limb regeneration

Increased expression of the pro-apoptotic Bcl2 family member PUMA and apoptosis by the muscle regulatory transcription factor MyoD in response to a variety of stimuli

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