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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Cadmium induced p53-dependent activation of stress signaling, accumulation of ubiquitinated proteins, and apoptosis in mouse embryonic fibroblast cells.

Authors: Yu, Xiaozhong; Sidhu, Jaspreet S; Hong, Sungwoo; Robinson, Joshua F; Ponce, Rafael A; Faustman, Elaine M

Published In Toxicol Sci, (2011 Apr)

Abstract: The tumor suppressor oncoprotein, p53, is a critical regulator of stress-induced growth arrest and apoptosis. p53 activity is regulated through the ubiquitin proteasome system (UPS) with stress-induced disruption leading to increased accumulation of p53, resulting in growth arrest. In the present study, we investigate the role of p53 to determine sensitivity to cadmium (Cd) and whether induction of stress signaling responses and perturbation of the UPS are involved in Cd-induced cytotoxicity and apoptosis. We treated synchronously cultured p53 transgenic mouse embryonic fibroblasts, both wild-type p53+/+ and knockout p53-/- cells, with cadmium chloride (Cd, 0.5-20ýýM) for 24 h. Cd-induced cytotoxicity was assessed by cellular morphology disruption and neutral red dye uptake assay. Proteins in the stress signaling pathway, including p38 mitogen-activated protein kinase (MAPK) and stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK); ubiquitination, such as high-molecular weight of polyubiquitinated proteins (HMW-polyUb); and apoptotic pathways, were all measured. We found that Cd induced p53-dependent cytotoxicity in the p53+/+ cells, which exhibited a twofold greater sensitivity. We observed a dose-dependent stimulation of p38 MAPK and SAPK/JNK phosphorylation that corresponded to accumulation of HMW-polyUb conjugates and lead to the induction of apoptosis, as evidenced by the elevation of cleaved caspase-3. Our study suggests that Cd-mediated cytotoxicity and induction of stress signaling responses, elevated accumulation of HMW-polyUb conjugates, and resulting apoptosis are all dependent on p53 status.

PubMed ID: 21252392 Exiting the NIEHS site

MeSH Terms: No MeSH terms associated with this publication

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