Conquering the complexity of p53

Attardi, Laura D.; DePinho, Ronald A.

doi:10.1038/ng0104-7

Cited by 17 publications

(14 citation statements)

References 15 publications

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“…Recent studies demonstrate that activation of the transcription factor p53 can promote apoptosis in renal ischemia (9,22). p53 and its transcriptional targets regulate diverse cellular functions that include cell cycle, senescence, differentiation, DNA repair, and apoptosis (1,3,29,43). p53 plays a critical role in the biochemical cascade that leads to apoptotic cell death following genotoxic insult and hypoxia (28).…”

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confidence: 99%

“…Although these p53 targets play cell type-specific roles in p53-mediated apoptosis, an obligatory role for any of these targets in p53-dependent apoptosis in all tissues is yet to be defined (17,18,42,49). It is proposed that the ability of p53 to initiate cell death in a particular tissue is related to the subset of p53 target genes that are up-or downregulated in response to apoptotic stimuli (1,29). The novel finding that p53 inhibitors protect against apoptosis (23) and renal dysfunction following ischemia-reperfusion (23) and cisplatin-induced injury (45) underscores the necessity to uncover the p53 target genes and the mechanisms by which they integrate their signals to execute p53-mediated apoptosis in renal ischemia (9).…”

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confidence: 99%

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PERP, a p53 proapoptotic target, mediates apoptotic cell death in renal ischemia

Singaravelu¹,

Devalaraja-Narashimha²,

Lastovica³

et al. 2009

American Journal of Physiology-Renal Physiology

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confidence: 99%

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PERP, a p53 proapoptotic target, mediates apoptotic cell death in renal ischemia

Singaravelu¹,

Devalaraja-Narashimha²,

Lastovica³

et al. 2009

American Journal of Physiology-Renal Physiology

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“…The present result suggest that Axin induces cell apoptosis and reduces the distribution of G2/M + S-phase cells by the p53 pathway. To achieve the role of p53 in tumor suppression, activated p53 seems to trigger two separable, albeit not mutually exclusive pathways, one to induce p21 for cell cycle arrest (32) and the other to induce proapoptotic factors such as Bax and Puma (33)(34)(35). Rui et al (11) showed that Axin and HIPK2 may preferentially trigger the apoptosis pathway but not the G1 cell cycle arrest pathway.…”

Section: Discussionmentioning

confidence: 99%

Axin induces cell death and reduces cell proliferation in astrocytoma by activating the p53 pathway

Zhang

Ye²,

Zhang³

et al. 2009

Int J Oncol

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Abstract. Astrocytic tumors are the most common brain tumors with various genetic defects. As a tumor suppressor gene, Axin could control cell death and growth. Axin possesses a separate domain that directly interacts with p53 and regulates the activity of p53 pathway. Our aims were to elucidate the effects of Axin on the progression of astrocytoma. We examined the expression of Axin in 96 cases of astrocytoma using immunohistochemistry. The apoptotic index, proliferactive acitivity and the expression levels of p53 and its downstream genes, p21 and Cyclin D1, were evaluated in the C6 astrocytoma cells with overexpression or silencing of Axin. The results showed the levels of Axin correlated significantly inversely with the grades of astrocytoma (R=-0.286, P<0.05) and correlated negatively with Ki-67 labeling index (R=-0.227, P<0.05). Overexpression of Axin in C6 cells induces cell death, and reduces the cell proliferation, up-regulates the expression of p53. Silencing of Axin reduces p53 expression. The p53 inhibitor, pifithrin-·, was able to counteract the effect of Axin in C6 cells. Our data demonstrate that the expression of Axin is associated negatively with the progression of astrocytoma. In conclusion, Axin induces cell death and reduces cell proliferation, partially by activating the p53 pathway in astrocytoma cells. This knowledge is helpful in understanding the role of Axin in the progression of astrocytoma.

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“…Physiologically, p53 induces cell-cycle arrest to enable repair of damaged components or, in the case of excessive damage, to induce cell death by apoptosis (13). p53 exerts its cell-cycle arrest and apoptotic functions in the nucleus, but it is shuttled to the cytoplasm where it can be retained, reshuttled to the nucleus, or destroyed (14).…”

Section: Introductionmentioning

confidence: 99%

Inactivation of the p53–KLF4–CEBPA Axis in Acute Myeloid Leukemia

Seipel

Marques

Bozzini

et al. 2016

Clinical Cancer Research

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Purpose: In acute myeloid leukemia (AML), the transcription factors CEBPA and KLF4 as well as the universal tumor suppressor p53 are frequently deregulated. Here, we investigated the extent of dysregulation, the molecular interactions, and the mechanisms involved.Experimental Design: One hundred ten AML patient samples were analyzed for protein levels of CEBPA, KLF4, p53, and p53 modulators. Regulation of CEBPA gene expression by KLF4 and p53 or by chemical p53 activators was characterized in AML cell lines.Results: We found that CEBPA gene transcription can be directly activated by p53 and KLF4, suggesting a p53-KLF4-CEBPA axis. In AML patient cells, we observed a prominent loss of p53 function and concomitant reduction of KLF4 and CEBPA protein levels. Assessment of cellular p53 modulator proteins indicated that p53 inactivation in leukemic cells correlated with elevated levels of the nuclear export protein XPO1/CRM1 and increase of the p53 inhibitors MDM2 and CUL9/PARC in the cytoplasm. Finally, restoring p53 function following treatment with cytotoxic chemotherapy compounds and p53 restoring nongenotoxic agents induced CEBPA gene expression, myeloid differentiation, and cell-cycle arrest in AML cells.Conclusions: The p53-KLF4-CEBPA axis is deregulated in AML but can be functionally restored by conventional chemotherapy and novel p53 activating treatments.

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Conquering the complexity of p53

Abstract: New evidence from a Trp53 'knock-in' mouse model suggests that p53-dependent cell cycle checkpoint control accompanied by maintenance of genome stability is important for keeping tumor growth in check.

Cited by 17 publications

References 15 publications

PERP, a p53 proapoptotic target, mediates apoptotic cell death in renal ischemia

PERP, a p53 proapoptotic target, mediates apoptotic cell death in renal ischemia

Axin induces cell death and reduces cell proliferation in astrocytoma by activating the p53 pathway

Inactivation of the p53–KLF4–CEBPA Axis in Acute Myeloid Leukemia

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