Involvement of p53-transactivated Puma in cisplatin-induced renal tubular cell death

Tsuruya, Kazuhiko; Yotsueda, Hideki; Ikeda, Hirofumi; Taniguchi, Masatomo; Masutani, Kohsuke; Hayashida, Hideko; Hirakata, Hideki; Iida, Mitsuo

doi:10.1016/j.lfs.2008.08.002

Cited by 31 publications

(28 citation statements)

References 32 publications

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“…12,23 In addition, p21, a p53 target gene involved in cell cycle arrest and cytoprotection, is induced markedly in various AKI models. 22,33,34 We, therefore, analyzed the expression of these genes to determine their dependence on proximal tubular p53. As shown in Figure 6, both p53 and its serine-15 phosphorylated form were induced by cisplatin in kidney cortical tissues in PTp53-WT mice.…”

Section: Resultsmentioning

confidence: 99%

“…Of note, both p53-dependent and -independent mechanisms contribute to p21 induction in AKI. 33 To further elucidate the p53-mediated gene expression in AKI, we conducted a global gene expression analysis using a cDNA microarray containing 26,515 genes. In wild-type mice, renal ischemiareperfusion for 24-48 hours led to the consistent induction of 341 genes.…”

Section: Discussionmentioning

confidence: 99%

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Tubular p53 Regulates Multiple Genes to Mediate AKI

Zhang

Liu

Wei

et al. 2014

Journal of the American Society of Nephrology

142

163

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A pathogenic role of p53 in AKI was suggested a decade ago but remains controversial. Indeed, recent work indicates that inhibition of p53 protects against ischemic AKI in rats but exacerbates AKI in mice. One intriguing possibility is that p53 has cell type-specific roles in AKI. To determine the role of tubular p53, we generated two conditional gene knockout mouse models, in which p53 is specifically ablated from proximal tubules or other tubular segments, including distal tubules, loops of Henle, and medullary collecting ducts. Proximal tubule p53 knockout (PT-p53-KO) mice were resistant to ischemic and cisplatin nephrotoxic AKI, which was indicated by the analysis of renal function, histology, apoptosis, and inflammation. However, other tubular p53 knockout (OT-p53-KO) mice were sensitive to AKI. Mechanistically, AKI associated with the upregulation of several known p53 target genes, including Bax, p53-upregulated modulator of apoptosis-a, p21, and Siva, and this association was attenuated in PT-p53-KO mice. In global expression analysis, ischemic AKI induced 371 genes in wild-type kidney cortical tissues, but the induction of 31 of these genes was abrogated in PT-p53-KO tissues. These 31 genes included regulators of cell death, metabolism, signal transduction, oxidative stress, and mitochondria. These results suggest that p53 in proximal tubular cells promotes AKI, whereas p53 in other tubular cells does not.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Tubular p53 Regulates Multiple Genes to Mediate AKI

Zhang

Liu

Wei

et al. 2014

Journal of the American Society of Nephrology

142

163

View full text Add to dashboard Cite

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“…p53 is activated early after cisplatin treatment of renal tubular cells in vitro and in animals in vivo (10,(15)(16)(17)(18)(19)(20)(21)(22). Pharmacological and genetic inhibition of p53 attenuates cisplatin-induced apoptosis in cultured tubular cells.…”

Section: Introductionmentioning

confidence: 99%

Untitled

Bhatt¹,

Mi²

2010

Mol. Med.

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MicroRNAs are small noncoding RNAs that are produced endogenously and have emerged as important regulators in pathophysiological conditions such as development and tumorigenesis. Very little is known about the regulation of microRNAs in renal diseases, including acute kidney injury (AKI). In this study, we examined the regulation of microRNA-34a (miR-34a) in experimental models of cisplatin-induced AKI and nephrotoxicity. By Northern blot and real-time polymerase chain reaction analyses, we detected an induction of miR-34a in vitro during cisplatin treatment of mouse proximal tubular cells and also in vivo during cisplatin nephrotoxicity in C57BL/6 mice. In cultured cells, miR-34a was induced within a few hours. In mice, miR-34a induction was detectable in renal tissues after 1 d of cisplatin treatment and increased to approximately four-fold of control at d 3. During cisplatin treatment, p53 was activated. Inhibition of p53 with pifithrin-α abrogated the induction of miR-34a during cisplatin treatment of proximal tubular cells. In vivo, miR-34a induction by cisplatin was abrogated in p53-deficient mice, a result that further confirms a role for p53 in miR-34a induction during cisplatin nephrotoxicity. Functionally, antagonism of miR-34a with specific antisense oligonucleotides increased cell death during cisplatin treatment. Collectively, the results suggest that miR-34a is induced via p53 during cisplatin nephrotoxicity and may play a cytoprotective role for cell survival.

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“…Distinct p53 target genes, such as Fas, FasL, Puma and Caspase-10, (15,(34)(35)(36)(37)94) were transcriptionally upregulated after drug treatment in the p53-proficient RT4 cells, but not in the p53-deficient T24 cells (Fig. 7), whereas both Bax and Noxa (other p53 targets) gene activities in response to the drug remained unaffected (data not shown), thereby allowing the association of T24 relative resistance to cisplatin toxicity with certain p53 target gene product cellular activities.…”

Section: Discussionmentioning

confidence: 99%

“…7) strongly supports the implication of its cognate protein product in the acquisition process of RT4 and T24 differential resistance to cisplatin activity. Puma, a bona fide p53 target gene (34,35), has been previously associated with cisplatin-mediated nephrotoxicity and renal tubular cell apoptosis through an activated p53-specific mechanism (15,36). Thereby, in contrast to T24, the putative upregulation and mitochondrial accumulation of Puma, BH3-only, protein in cisplatin-treated RT4 cells could result in a severe neutralization of the Bcl-2 family-based anti-apoptotic functions and a Bax-mediated release of Cytochrome c into the cytosol, followed by Caspase maturation and activation of apoptosis, as previously demonstrated for other cellular systems (15,26,31).…”

Section: Discussionmentioning

confidence: 99%

Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses

Konstantakou

Voutsinas²,

Karkoulis³

et al. 2009

Int J Oncol

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Abstract.Cisplatin is a first-line chemotherapeutic agent and a powerful component of standard treatment regimens for several human malignancies including bladder cancer. DNAPt adducts produced by cisplatin are mainly responsible for cellular toxicity and induction of apoptosis. Identification of the mechanisms that control sensitivity to cisplatin is central to improving its therapeutic index and to successfully encountering the acquired resistance frequently emerging during therapy. In the present study, using MTT-based assays, Western blotting and semi-quantitative RT-PCR, we examined the apoptosis-related cellular responses to cisplatin exposure in two human urinary bladder cancer cell lines characterized by different malignancy grade and p53 genetic status. Both RT4 (grade I; wild-type p53) and T24 (grade III; mutant p53) cell types proved to be vulnerable to cisplatin apoptotic activity, albeit in a grade-dependent and drug dose-specific manner, as demonstrated by the proteolytic processing profiles of Caspase-8, Caspase-9, Caspase-3, and the Caspase repertoire characteristic substrates PARP and Lamin A/C, as well. The differential resistance of RT4 and T24 cells to cisplatin-induced apoptosis was associated with an RT4-specific phosphorylation (Ser15; Ser392) pattern of p53, together with structural amputations of the Akt and XIAP anti-apoptotic regulators. Furthermore, cisplatin administration resulted in a Granzyme B-mediated proteolytic cleavage of Hsp90 molecular chaperone, exclusively occurring in RT4 cells. To generate functional networks, expression analysis of a number of genes, including Bik, Bim, Fas, FasL, TRAIL, Puma, ATP7A, ATP7B and MRP1, was performed, strongly supporting the role of p53-dependent and p53-independent transcriptional responses in cisplatin-induced apoptosis of bladder cancer cells. IntroductionWith its incidence continuing to increase, bladder cancer is classified among the five most common malignancies in industrialized countries (1). Forming a worldwide estimate over one million patients, bladder cancer is clearly considered a significant public health issue around the world (2). The three main types of cancer affecting bladder are transitional cell carcinoma (TCC), squamous cell carcinoma (SCC) and adenocarcinoma (ADC), with TCC representing >90% of all bladder cancers. Four clinically distinct entities of TCC have been recognized: superficial, papillary tumors (Ta and T1), carcinoma in situ (Tis), muscle-invasive tumors (T2-T4) and advanced disease, involving extra-pelvic nodal or distant metastasis (3,4). Metastatic TCC demonstrates a moderate sensitivity to chemotherapy while a significant variation in patient survival rates and activity levels of individual regimens has been observed (5).Cisplatin-based combination chemotherapy protocols, such as MVAC (methotrexate-vinblastine-adriamycin-cisplatin), constituted for a number of years standard treatment of patients with advanced (or metastatic) urothelial bladder cancer. However, due to the MVAC-induced systemic toxici...

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Involvement of p53-transactivated Puma in cisplatin-induced renal tubular cell death

Cited by 31 publications

References 32 publications

Tubular p53 Regulates Multiple Genes to Mediate AKI

Tubular p53 Regulates Multiple Genes to Mediate AKI

Untitled

Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses

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