Advanced SearchSearch Tips
Different Regulation of p53 Expression by Cadmium Exposure in Kidney, Liver, Intestine, Vasculature, and Brain Astrocytes
facebook(new window)  Pirnt(new window) E-mail(new window) Excel Download
  • Journal title : Toxicological Research
  • Volume 32, Issue 1,  2016, pp.73-80
  • Publisher : The Korean Society of Toxicology
  • DOI : 10.5487/TR.2016.32.1.073
 Title & Authors
Different Regulation of p53 Expression by Cadmium Exposure in Kidney, Liver, Intestine, Vasculature, and Brain Astrocytes
Lee, Jin-Yong; Tokumoto, Maki; Hattori, Yuta; Fujiwara, Yasuyuki; Shimada, Akinori; Satoh, Masahiko;
  PDF(new window)
Chronic exposure to cadmium (Cd) is known to adversely affect renal function. Our previous studies indicated that Cd induces p53-dependent apoptosis by inhibiting gene expression of the ubiquitin-conjugating enzyme (Ube) 2d family in both human and rat proximal tubular cells. In this study, the effects of Cd on protein expression of p53 and apoptotic signals in the kidney and liver of mice exposed to Cd for 12 months were examined, as well as the effects of Cd on p53 protein levels and gene expression of the Ube2d family in various cell lines. Results showed that in the kidney of mice exposed to 300 ppm Cd for 12 months, there was overaccumulation of p53 proteins in addition to the induction of apoptosis, which was triggered specifically in the proximal tubules. Interestingly, the site of apoptosis was the same as that of p53 accumulation in the proximal tubules. In the liver of mice chronically exposed to Cd, gene expression of the Ube2d family tended to be slightly decreased, together with slight apoptosis without the accumulation of p53 protein. In rat small intestine epithelial (IEC-6) cells, Cd decreased not only the p53 protein level but also gene expression of Ube2d1, Ube2d2 and Ube2d4. In human brain microvascular endothelial cells (HBMECs), Cd did not suppress gene expression of the Ube2d family, but increased the p53 protein level. In human brain astrocytes (HBASTs), Cd only increased gene expression of UBE2D3. These results suggest that Cd-induced apoptosis through p53 protein is associated with renal toxicity but not hepatic toxicity, and the modification of p53 protein by Cd may vary depending on cell type.
Cadmium;p53 protein;Ube2d family;Apoptosis;Renal toxicity;
 Cited by
Shedding New Lights with the Breakthrough Ideas to Understand Current Trends in Modern Toxicology, Toxicological Research, 2016, 32, 1, 1  crossref(new windwow)
Heme oxygenase-1-mediated apoptosis under cadmium-induced oxidative stress is regulated by autophagy, which is sensitized by tumor suppressor p53, Biochemical and Biophysical Research Communications, 2016, 479, 1, 80  crossref(new windwow)
Van Maele-Fabry, G., Lombaert, N. and Lison, D. (2016) Dietary exposure to cadmium and risk of breast cancer in postmenopausal women: A systematic review and meta-analysis. Environ. Int., 86, 1-13. crossref(new window)

Nair, A.R., Degheselle, O., Smeets, K., Van Kerkhove, E. and Cuypers, A. (2013) Cadmium-induced pathologies: Where is the oxidative balance lost (or Not). Int. J. Mol. Sci., 14, 6116-6143. crossref(new window)

Ninkov, M., Popov Aleksandrov, A., Demenesku, J., Mirkov, I., Mileusnic, D., Petrovic, A., Grigorov, I., Zolotarevski, L., Tolinacki, M., Kataranovski, D., Brceski, I. and Kataranovski, M. (2015) Toxicity of oral cadmium intake: Impact on gut immunity. Toxicol. Lett., 237, 89-99. crossref(new window)

Jarup, L. and Akesson, A. (2009) Current status of cadmium as an environmental health problem. Toxicol. Appl. Pharmacol., 238, 201-208. crossref(new window)

Fujiwara, Y., Lee, J.Y., Tokumoto, M. and Satoh, M. (2012) Cadmium renal toxicity via apoptotic pathways. Biol. Pharm. Bull., 35, 1892-1897. crossref(new window)

Tokumoto, M., Fujiwara, Y., Shimada, A., Hasegawa, T., Seko, Y., Nagase, H. and Satoh, M. (2011) Cadmium toxicity is caused by accumulation of p53 through the down-regulation of Ube2d family genes in vitro and in vivo. J. Toxicol. Sci., 36, 191-200. crossref(new window)

Haupt, Y., Maya, R., Kazaz, A. and Oren, M. (1997) Mdm2 promotes the rapid degradation of p53. Nature, 387, 296-299. crossref(new window)

Honda, R., Tanaka, H. and Yasuda, H. (1997) Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett., 420, 25-27. crossref(new window)

Kubbutat, M.H., Jones, S.N. and Vousden, K.H. (1997) Regulation of p53 stability by Mdm2. Nature, 387, 299-303. crossref(new window)

Saville, M.K., Sparks, A., Xirodimas, D.P., Wardrop, J., Stevenson, L.F., Bourdon, J.C., Woods, Y.L. and Lane, D.P. (2004) Regulation of p53 by the ubiquitin-conjugating enzymes UbcH5B/C in vivo. J. Biol. Chem., 279, 42169-42181. crossref(new window)

Swiergosz-Kowalewska, R. (2001) Cadmium distribution and toxicity in tissues of small rodents. Microsc. Res. Tech., 55, 208-222. crossref(new window)

Lee, J.Y., Tokumoto, M., Fujiwara, Y. and Satoh, M. (2015) Involvement of ubiquitin-coding genes in cadmium-induced protein ubiquitination in human proximal tubular cells. J. Toxicol. Sci., 40, 901-908. crossref(new window)

Du, K., Takahashi, T., Kuge, S., Naganuma, A. and Hwang, G.W. (2014) FBXO6 attenuates cadmium toxicity in HEK293 cells by inhibiting ER stress and JNK activation. J. Toxicol. Sci., 39, 861-866. crossref(new window)

Urani, C., Melchioretto, P., Fabbri, M., Bowe, G., Maserati, E. and Gribaldo, L. (2014) Cadmium impairs p53 activity in HepG2 cells. ISRN Toxicol., 2014, 976428.

Bhattacharya, S., Ray, R.M. and Johnson, L.R. (2014) Cyclin dependent kinases regulate apoptosis of intestinal epithelial cells. Apoptosis, 19, 451-466. crossref(new window)

Jung, Y.S., Jeong, E.M., Park, E.K., Kim, Y.M., Sohn, S., Lee, S.H., Baik, E.J. and Moon, C.H. (2008) Cadmium induces apoptotic cell death through p38 MAPK in brain microvessel endothelial cells. Eur. J. Pharmacol., 578, 11-18. crossref(new window)

Jeong, E.M., Moon, C.H., Kim, C.S., Lee, S.H., Baik, E.J., Moon, C.K. and Jung, Y.S. (2004) Cadmium stimulates the expression of ICAM-1 via NF-kappaB activation in cerebrovascular endothelial cells. Biochem. Biophys. Res. Commun., 320, 887-892. crossref(new window)

Yang, C.S., Tzou, B.C., Liu, Y.P., Tsai, M.J., Shyue, S.K. and Tzeng, S.F. (2008) Inhibition of cadmium-induced oxidative injury in rat primary astrocytes by the addition of antioxidants and the reduction of intracellular calcium. J. Cell. Biochem., 103, 825-834. crossref(new window)

Jo, C. and Koh, Y.H. (2013) Cadmium induces N-cadherin cleavage via ERK-mediated $\gamma$-secretase activation in C6 astroglia cells. Toxicol. Lett., 222, 117-121. crossref(new window)

Tokumoto, M., Lee, J.Y., Fujiwara, Y. and Satoh, M. (2014) Alteration of DNA binding activity of transcription factors in NRK-52E rat proximal tubular cells treated with cadmium. J. Toxicol. Sci., 39, 735-738. crossref(new window)