The clusterin (CLU) protein has been reported to have both cytoprotective and cytotoxic activities. Previous data from our lab suggest that the secretory form of CLU (sCLU) is cytoprotective and induced after very low, nontoxic doses of ionizing radiation (IR: >0.02 Gy), while a nuclear form is cytotoxic.1 Cells must presumably suppress sCLU to stimulate cell death, however, factors regulating the stress-inducible expression of sCLU have not been elucidated. Here we demonstrate that p53 can suppress sCLU induction responses. A variety of cytotoxic agents stimulated sCLU expression and DNA damage was sufficient but not necessary for induction. IR-stimulated CLU promoter activity, with concomitant increases in CLU mRNA and protein, showed that CLU induction was delayed with maximal expression observed 48-96 h post-treatment. Expression of the human papillomavirus E6 protein in MCF-7 breast or RKO colon cancer cells enhanced basal CLU levels. Isogenically matched HCT116 colon cancer cell lines that differed only in p53 or p21 status, confirmed a role for p53 in the transcriptional repression of sCLU. Loss of functional p53 in HCT116:p53-/- cells augmented CLU de novo synthesis after IR exposure. Repression of sCLU protein levels by p53 may be important for the cascade of p53-mediated events leading to cell death after IR or other cytotoxic agent exposure.