Accumulation of p53 via down-regulation of UBE2D family genes is a critical pathway for cadmium-induced renal toxicity

Jin-Yong Lee; Maki Tokumoto; Yasuyuki Fujiwara; Tatsuya Hasegawa; Yoshiyuki Seko; Akinori Shimada; Masahiko Satoh

doi:10.1038/srep21968

Accumulation of p53 via down-regulation of UBE2D family genes is a critical pathway for cadmium-induced renal toxicity

Sci Rep. 2016 Feb 25:6:21968. doi: 10.1038/srep21968.

Authors

Jin-Yong Lee¹, Maki Tokumoto¹, Yasuyuki Fujiwara^{1

2}, Tatsuya Hasegawa³, Yoshiyuki Seko³, Akinori Shimada⁴, Masahiko Satoh¹

Affiliations

¹ Laboratory of Pharmaceutical Health Sciences, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, Aichi 464-8650, Japan.
² Department of Environmental Health, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
³ Department of Environmental Biochemistry, Mount Fuji Research Institute, 5597-1 Kenmarubi, Kamiyoshida, Fujiyoshida, Yamanashi 403-0005, Japan.
⁴ Laboratory of Pathology, Department of Medical Technology, School of Life and Environmental Science, Azabu University, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan.

Abstract

Chronic cadmium (Cd) exposure can induce renal toxicity. In Cd renal toxicity, p53 is thought to be involved. Our previous studies showed that Cd down-regulated gene expression of the UBE2D (ubiquitin-conjugating enzyme E2D) family members. Here, we aimed to define the association between UBE2D family members and p53-dependent apoptosis in human proximal tubular cells (HK-2 cells) treated with Cd. Cd increased intracellular p53 protein levels and decreased UBE2D2 and UBE2D4 gene expression via inhibition of YY1 and FOXF1 transcription factor activities. Double knockdown of UBE2D2 and UBE2D4 caused an increase in p53 protein levels, and knockdown of p53 attenuated not only Cd-induced apoptosis, but also Cd-induced apoptosis-related gene expression (BAX and PUMA). Additionally, the mice exposed to Cd for 6 months resulted in increased levels of p53 and induction of apoptosis in proximal tubular cells. These findings suggest that down-regulation of UBE2D family genes followed by accumulation of p53 in proximal tubular cells is an important mechanism for Cd-induced renal toxicity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects*
Apoptosis Regulatory Proteins / metabolism
Base Sequence
Blotting, Western
Cadmium / toxicity*
Cell Line
Down-Regulation / drug effects*
Female
Forkhead Transcription Factors / antagonists & inhibitors
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism
Humans
Kidney / drug effects
Kidney / metabolism
Kidney / pathology
Mice
Mice, Inbred C57BL
Microscopy, Fluorescence
Proto-Oncogene Proteins / metabolism
RNA Interference
RNA, Small Interfering / metabolism
Real-Time Polymerase Chain Reaction
Tumor Suppressor Protein p53 / antagonists & inhibitors
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism*
Ubiquitin-Conjugating Enzymes / antagonists & inhibitors
Ubiquitin-Conjugating Enzymes / genetics
Ubiquitin-Conjugating Enzymes / metabolism*
YY1 Transcription Factor / antagonists & inhibitors
YY1 Transcription Factor / genetics
YY1 Transcription Factor / metabolism
bcl-2-Associated X Protein / metabolism

Substances

Apoptosis Regulatory Proteins
BBC3 protein, human
FOXF1 protein, human
Forkhead Transcription Factors
Proto-Oncogene Proteins
RNA, Small Interfering
Tumor Suppressor Protein p53
YY1 Transcription Factor
bcl-2-Associated X Protein
Cadmium
UBE2D2 protein, human
Ubiquitin-Conjugating Enzymes