p21WAF1 induces permanent growth arrest and enhances differentiation, but does not alter apoptosis in PC12 cells

Erhardt, Joseph A.; Pittman, Randall N.

doi:10.1038/sj.onc.1201577

Cited by 53 publications

(52 citation statements)

References 40 publications

(50 reference statements)

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“…PD98059 did not alleviate the growth arrest phenotype detectably (data not shown). This result may reflect the fact that the growth arrest phenotype can be induced independently by p21 (29)(30)(31).…”

Section: Resultsmentioning

confidence: 94%

Sustained activation of Ras/Raf/mitogen-activated protein kinase cascade by the tumor suppressor p53

Lee

Igarashi

et al. 2000

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

101

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The p53 tumor suppressor gene can inhibit proliferation transiently, induce permanent cell-cycle arrest͞senescence, or cause apoptosis depending on the cellular context. The mitogen-activated protein kinase (MAPK) cascade is known to play a crucial role in cell proliferation and differentiation. Moreover, the duration and intensity of MAPK activation can profoundly influence the biological response observed. We demonstrated that a sustained activation of MAPK cascade could be induced by wild-type p53 expression but not by p21 Waf1͞Cip1 . Furthermore, exposure of normal cells to DNA-damaging agents induced MAPK activation in a p53-dependent manner. Tumor-derived p53 mutants defective in DNA binding failed to activate MAPK, implying that p53 transcriptional activity is essential for this function. Finally, activation of MAPK by p53 was inhibited by expression of dominant-negative Ras (N17Ras) and Raf1 mutants, indicating that MAPK activation by p53 is mediated at a level upstream of Ras. All of these findings establish a biochemical link between p53 signaling and the Ras͞ Raf͞MAPK cascade.

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Section: Resultsmentioning

confidence: 94%

Sustained activation of Ras/Raf/mitogen-activated protein kinase cascade by the tumor suppressor p53

Lee

Igarashi

et al. 2000

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

101

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“…While about 24% of uninduced cells appeared at S phase at 24 h, only 13% of TrkA-induced cells were with S phase, suggesting that TrkA is involved in suppression of G1 to S phase cell cycle progression. In Figure 1, we showed that TrkA overexpression induced p21, which is a key factor for cell cycle arrest (Erhardt and Pittman, 1998). This fact suggests that TrkA could inhibit cell cycle progression through, at least in part, p21 upregulation.…”

Section: Trka Overexpression Promotes Cell Death Through Cell Cycle Amentioning

confidence: 85%

Cytosolic accumulation of γH2AX is associated with tropomyosin-related kinase A-induced cell death in U2OS cells

Jung

Kim

2008

Exp Mol Med

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Tropomyosin-related kinase A (TrkA) plays an important role in cell survival, differentiation, and apoptosis in various neuronal and nonneuronal cell types. Here we show that TrkA overexpression by the Tet-On system mimics NGF-mediated activation pathways in the absence of nerve growth factor (NGF) stimulation in U2OS cells. In addition, p53 upregulation upon DNA damage was inhibited by TrkA, and p21 was upregulated by TrkA in a p53-independent manner. TrkA overexpression caused cell death by interrupting cell cycle progression, and TrkA-induced cell death was diminished in the presence of its specific inhibitor GW441756. Interestingly, TrkA-mediated cell death was strongly related to γH2AX production and poly (ADP-ribose) polymerase cleavage in the absence of DNA damage inducer. In this study, we also reveal that γH2AX production by TrkA is blocked by TrkA kinase inhibitors K-252a and GW441756, and it is also significantly inhibited by JNK inhibitor SP600125. Moreover, reduction of cell viability by TrkA was strongly suppressed by SP600125 treatment, suggesting a critical role of JNK in TrkA-induced cell death. We also found that γH2AX and TrkA were colocalized in cytosol in the absence of DNA damage, and the nuclear localization of γH2AX induced by DNA damage was partly altered to cytosol by TrkA overexpression. Our results suggest that the abnormal cytosolic accumulation of γH2AX is implicated in TrkA-induced cell death in the absence of DNA damage.

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“…In this model, during NGF-induced di erentiation, neurite outgrowth is inhibited by those domains of the viral oncoprotein E1A that bind to and inactivate pRb, pRb2/p130 and p300 (Kalman et al, 1993), con®rming a relevant role in neural di erentiation program for these regulators. NGF induces p21 and cyclin D1 transcription in PC12 cells (Yan and Zi , 1997), but ectopic p21 overexpression, while causing a permanent cell-cycle arrest, thus accelerating NGF-dependent di erentiation, is not su cient per se to establish a di erentiation program (Van Grunsven et al, 1996;Erhardt and Pittman, 1998). Our results with PC12 cells showed that NGF treatment increased Rb2-p130 transcription and AP-2 and pRb2/p130 protein levels and that AP-2 or Rb2/p130 overexpression was able per se to induce di erentiation.…”

Section: Discussionmentioning

confidence: 99%

The retinoblastoma-related Rb2/p130 gene is an effector downstream of AP-2 during neural differentiation

Paggi¹,

Bonetto²,

Severino³

et al. 2001

Oncogene

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Rb2/p130, a member of the Retinoblastoma family of growth and tumour suppressor genes, is extensively implicated in the control of cell cycle and di erentiation. The minimal promoter region of Rb2/p130 in T98G human glioblastoma cells was identi®ed and its analysis revealed the presence of a KER1 palindromic sequence able to bind the transcription factor AP-2, a regulatory protein that plays a crucial role in ectodermal di erentiation. This KER1 site interacted in vitro with AP-2, and AP-2 overexpression increased Rb2/p130 transcription and translation. We also found that rat PC12 pheochromocytoma cells, when induced to di erentiate by NGF, displayed an increase of AP-2 protein levels and of Rb2/p130 transcription and protein levels. AP-2-transfected PC12 cells displayed enhanced transcription and translation of Rb2/p130 and of the cdk inhibitor p21 WAF1/CIP1 , a gene known to be under the control of AP-2, but unable by itself to elicit PC12 di erentiation. Overexpression of either AP-2 or Rb2/p130 elicited per se cell di erentiation in the absence of NGF, while coexpression of AP-2B, a negative regulator of AP-2 transcriptional activity, inhibited only AP-2-induced di erentiation. Altogether, these results indicate that Rb2/p130 is a critical e ector of AP-2 in sustaining ectodermal di erentiation. Oncogene (2001) 20, 2570 ± 2578.

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p21WAF1 induces permanent growth arrest and enhances differentiation, but does not alter apoptosis in PC12 cells

Cited by 53 publications

References 40 publications

Sustained activation of Ras/Raf/mitogen-activated protein kinase cascade by the tumor suppressor p53

Sustained activation of Ras/Raf/mitogen-activated protein kinase cascade by the tumor suppressor p53

Cytosolic accumulation of γH2AX is associated with tropomyosin-related kinase A-induced cell death in U2OS cells

The retinoblastoma-related Rb2/p130 gene is an effector downstream of AP-2 during neural differentiation

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