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

Abstract

AIMS:

The tumor suppressor protein p53 plays a critical role as a determinant of cell survival when cells are exposed to various toxic stresses, by preventing growth arrest, replication of damaged DNA, and apoptosis. A novel p53-dependent proapoptotic gene, Puma (p53 upregulated modulator of apoptosis) is thought to participate in this process. Recently, p53 was reported to play an essential role in cisplatin-induced renal tubular cell (RTC) death. The objective of the present study was to elucidate the roles of p53 and Puma in cisplatin-induced RTC death.

MAIN METHODS:

We examined the in vivo expression of p53 and Puma-alpha in the kidney and evaluated the modification of Puma-alpha expression and RTC death by in vitro treatment with pifithrin-alpha (PFT-alpha), a specific p53 inhibitor, or Puma-alpha-specific small interfering RNA (siRNA).

KEY FINDINGS:

While no immunoreactivity for anti-p53- and anti-Puma-alpha antibody was detected in the control rat kidney, de novo expression of p53 and Puma-alpha was identified in the proximal tubular cells of the outer medulla at 6 h after cisplatin injection. Upregulation of these proteins preceded severe RTC injury. In vitro experiments revealed that PFT-alpha inhibited upregulation of Puma-alpha, and inhibition of Puma-alpha, either by PFT-alpha or by Puma-alpha-specific siRNA, decreased RTC death induced by 24-h cisplatin exposure.

SIGNIFICANCE:

Our results indicated that p53 activation mediated cisplatin-induced RTC death through upregulation of Puma, and suggested that inhibition of p53 and Puma is beneficial for the prevention and treatment of cisplatin-induced acute renal failure.

• Authors: Kazuhiko Tsuruya, Hideki Yotsueda, Hirofumi Ikeda, Masatomo Taniguchi, Kohsuke Masutani, Hideko Hayashida, Hideki Hirakata, Mitsuo Iida
• Journal: Life sciences (Life Sci) Vol. 83 Issue 15-16 Pg. 550-6 (Oct 10 2008) ISSN: 0024-3205 [Print] Netherlands
• PMID: 18761355 (Publication Type: Journal Article)

Chemical References

• Actins
• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• Bbc3 protein, rat
• RNA, Small Interfering
• L-Lactate Dehydrogenase
• Glyceraldehyde-3-Phosphate Dehydrogenases
• Cisplatin

Topics

• Actins (metabolism)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis Regulatory Proteins (antagonists & inhibitors, physiology)
• Cell Death (drug effects)
• Cell Line
• Cell Survival (drug effects)
• Cisplatin (pharmacology)
• Epithelial Cells (drug effects)
• Genes, p53 (drug effects)
• Glyceraldehyde-3-Phosphate Dehydrogenases (metabolism)
• Immunohistochemistry
• Kidney Tubules (cytology, drug effects)
• L-Lactate Dehydrogenase (metabolism)
• Male
• RNA, Small Interfering (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Reverse Transcriptase Polymerase Chain Reaction
• Transcriptional Activation (drug effects)