MyoD induces apoptosis in the absence of RB function through a p21WAF1-dependent re-localization of cyclin/cdk complexes to the nucleus

Peschiaroli, Angelo; Figliola, Rocco; Coltella, Luana; Strom, Alessandra; Valentini, Alessandra; D’Agnano, Igea; Maione, Rossella

doi:10.1038/sj.onc.1206010

Cited by 34 publications

(34 citation statements)

References 66 publications

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“…The survival effect of P21 waf1/cip1 has been reported to be linked to cytoplasmic localization (Asada et al, 1999;Coqueret, 2003), whereas the apoptotic effect of P21 waf1/cip1 would occur when P21 waf1/cip1 is present in the nucleus (Ritt et al, 2000;Peschiaroli et al, 2002). In accordance with these reports, we showed that NaB-induced apoptosis was associated with an increase of P21 waf1/cip1 , particularly in the nucleus.…”

Section: Discussionsupporting

confidence: 81%

P21WAF1/CIP1 is dispensable for G1 arrest, but indispensable for apoptosis induced by sodium butyrate in MCF-7 breast cancer cells

et al. 2004

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Sodium butyrate (NaB) has been proposed as a potential anticancer agent. However, its mechanism of action is not totally elucidated. Here, we showed that NaB-induced cell cycle arrest and apoptosis were associated with an increase of P21 waf1/cip1 in MCF-7 breast cancer cells. This increase was more important in the nuclei, as revealed by immunofluorescence analysis. Transient transfections of MCF-7 cells with p21 deficient for interaction with CDK, but not with p21 deficient for interaction with PCNA (p21PCNAÀ), abrogated NaB-induced cell cycle arrest. This indicated that cell cycle blockage involved the interaction of P21 waf1/cip1 with CDK. However, P21waf1/cip1 was dispensable, since p21 antisense did not modify cell cycle arrest. On the other hand, NaB-induced apoptosis was abolished by p21 antisense or p21PCNAÀ. In addition, NaB decreased PCNA levels, but increased the association of PCNA with P21 waf1/cip1. These results suggested that NaB-induced apoptosis required P21 waf1/cip1 and its interaction with PCNA.

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Section: Discussionsupporting

confidence: 81%

P21WAF1/CIP1 is dispensable for G1 arrest, but indispensable for apoptosis induced by sodium butyrate in MCF-7 breast cancer cells

et al. 2004

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“…It was thus unexpected to find a high level of p21 together with a large pool of hyper-ppRb in clones expressing R453W-lamin A. This apparent discrepancy may be explained by the dual role of p21, which, besides its function as a cdk inhibitor, can induce nuclear accumulation and aberrant activity of cyclin-cdk complexes in the presence of MyoD and in the absence of functional pRb, resulting in increased apoptosis frequency (44).…”

Section: Vol 24 2004 Mutation In Lamin a Inhibits In Vitro Myogenesmentioning

confidence: 97%

“…Terminal muscular differentiation is a stepwise process. At an early stage, MyoD directly upregulates pRb, p21, cyclin D3, and myogenin expression in a Rb-independent manner (1,7,39,44). Subsequently, activation of late differentiation genes in normal cells is induced by both myogenin and MyoD.…”

Section: Vol 24 2004 Mutation In Lamin a Inhibits In Vitro Myogenesmentioning

confidence: 99%

Expression of a Mutant Lamin A That Causes Emery-Dreifuss Muscular Dystrophy Inhibits In Vitro Differentiation of C2C12 Myoblasts

Favreau

Higuet

Courvalin

et al. 2004

Molecular and Cellular Biology

129

102

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Autosomal dominantly inherited missense mutations in lamins A and C cause several tissue-specific diseases, including Emery-Dreifuss muscular dystrophy (EDMD) and Dunnigan-type familial partial lipodystrophy (FPLD).Here we analyze myoblast-to-myotube differentiation in C2C12 clones overexpressing lamin A mutated at arginine 453 (R453W), one of the most frequent mutations in EDMD. In contrast with clones expressing wild-type lamin A, these clones differentiate poorly or not at all, do not exit the cell cycle properly, and are extensively committed to apoptosis. These disorders are correlated with low levels of expression of transcription factor myogenin and with the persistence of a large pool of hyperphosphorylated retinoblastoma protein. Since clones mutated at arginine 482 (a site responsible for FPLD) differentiate normally, we conclude that C2C12 clones expressing R453W-mutated lamin A represent a good cellular model to study the pathophysiology of EDMD. Our hypothesis is that lamin A mutated at arginine 453 fails to build a functional scaffold and/or to maintain the chromatin compartmentation required for differentiation of myoblasts into myocytes.Lamins A and C are nuclear intermediate filament proteins that are expressed in nearly all somatic cells. Mutations in these proteins cause diseases that affect striated muscle, adipose tissue, peripheral nerves, or skeletal development (56). Hutchinson-Gilford progeria syndrome, a form of accelerated aging in childhood, has been recently shown to be due to mutations in lamin A (13, 16). Three muscular diseases, EmeryDreifuss muscular dystrophy (EDMD), dilated cardiomyopathy with conduction defect 1, and limb girdle muscular dystrophy type 1B, are dominant. Mice lacking A-type lamins or deficient in prelamin A maturation develop skeletal and cardiac lethal muscular dystrophies soon after birth, confirming the importance of A-type lamins for muscle differentiation and/or maintenance (43, 51). However, the mechanisms by which mutations in these ubiquitous proteins generate tissuespecific diseases are presently unknown.In all metazoan nuclei, lamins form a meshwork (named the nuclear lamina) located between the inner nuclear membrane and chromatin (50). Lamins interact with both integral proteins of this membrane and DNA and chromatin proteins (49, 55). Two types of lamins are present in somatic cells of vertebrates. A-type lamins (lamin A, lamin C, and lamin ⌬10) are somatic cell isoforms arising by alternative splicing from the LMNA gene located on chromosome 1q21.2 (21,29,30,35,57). Lamin A and lamin C are identical over their first 566 amino acids. A-type lamins are not expressed in early embryos or in adult stem cells and become progressively expressed during development and cell differentiation (50). B-type lamins (B1 and B2) that are encoded by different genes are constitutively expressed in all cell types (2). Like all intermediate filament proteins, lamins have a conserved central ␣-helical domain that is responsible for the formation of coiled-coil dimers f...

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“…The role of p21 Cip1 in lymphocytes is less clear. Various reports suggest that p21 Cip1 may act to inhibit apoptosis (8), promote cell cycle withdrawal upon prolonged stimulation (9), or promote apoptosis (10). More recent data suggest that p21 Cip1 plays a role in Fas-mediated activation-induced cell death (11,12).…”

mentioning

confidence: 99%

p21Cip1 and p27Kip1 Act in Synergy to Alter the Sensitivity of Naive T Cells to TGF-β-Mediated G1 Arrest through Modulation of IL-2 Responsiveness

Wolfraim

Walz

James

et al. 2004

The Journal of Immunology

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Induction of G1 arrest by TGF-β correlates with the regulation of p21Cip1 and p27Kip1, members of the Cip/Kip family of cyclin-dependent kinase inhibitors (cki). However, no definitive evidence exists that these proteins play a causal role in TGF-β1-induced growth arrest in lymphocytes. In this report we show the suppression of cell cycle progression by TGF-β is diminished in T cells from mice deficient for both p21Cip1 and p27Kip1 (double-knockout (DKO)) only when activated under conditions of optimal costimulation. Although there is an IL-2-dependent enhanced proliferation of CD8+ T cells from DKO mice, TGF-β is able to maximally suppress the proliferation of DKO T cells when activated under conditions of low costimulatory strength. We also show that the induction of p15Ink4b in T cells stimulated in the presence of TGF-β is not essential, as TGF-β also efficiently suppressed proliferation of T cells from p15Ink4b−/− mice. Finally, although these cki are dispensable for the suppression of T cell proliferation by TGF-β, we now describe a Smad3-dependent down-regulation of cdk4, suggesting a potential mechanism underlying to resistance of Smad3−/− T cells to the induction of growth arrest by TGF-β. In summary, the growth suppressive effects of TGF-β in naive T cells are a function of the strength of costimulation, and alterations in the expression of cki modify the sensitivity to TGF-β by lowering thresholds for a maximal mitogenic response.

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MyoD induces apoptosis in the absence of RB function through a p21WAF1-dependent re-localization of cyclin/cdk complexes to the nucleus

Cited by 34 publications

References 66 publications

P21WAF1/CIP1 is dispensable for G1 arrest, but indispensable for apoptosis induced by sodium butyrate in MCF-7 breast cancer cells

P21WAF1/CIP1 is dispensable for G1 arrest, but indispensable for apoptosis induced by sodium butyrate in MCF-7 breast cancer cells

Expression of a Mutant Lamin A That Causes Emery-Dreifuss Muscular Dystrophy Inhibits In Vitro Differentiation of C2C12 Myoblasts

p21Cip1 and p27Kip1 Act in Synergy to Alter the Sensitivity of Naive T Cells to TGF-β-Mediated G1 Arrest through Modulation of IL-2 Responsiveness

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