Differential regulation of the clusterin gene by Ha-ras and c-myc oncogenes and during apoptosis

Abstract

Clusterin (ApoJ) is an extracellular glycoprotein expressed during processes of tissue differentiation and regression that involve programmed cell death (apoptosis). Increased clusterin expression has also been found in tumors, however, the mechanism underlying this induction is not known. Apoptotic processes in tumors could be responsible for clusterin gene activation. Alternatively, oncogenic mutations could modulate signal transduction, thereby inducing the gene. We examined the response of the rat clusterin gene to two oncogenes, Ha-ras and c-myc, in transfected Rat1 fibroblasts. While c-myc overexpression did not modify clusterin gene activity, the Ha-ras oncogene produced a seven to tenfold repression of clusterin mRNA; this down-regulation was also observed in the presence of c-myc. Since no induction of the clusterin gene was observed by the two oncogenes, we tested the alternative mechanism involving apoptosis. Growth factor withdrawal induced apoptosis, as shown by DNA degradation and micronuclei formation in the floating cells. Concomittantly we observed a three to tenfold increase in the amount of clusterin mRNA in the adhering cells of Rat1 and the c-myc transformed cell lines, and a weaker induction in the Ha-ras transformed cell line. On the basis of our results, we suggest that clusterin gene induction in the vital cells is produced by signaling molecules that are generated by the apoptotic cells. We conclude that apoptotic processes, not oncogenic mutations, are responsible for increased clusterin expression in tumors.

Ras activation is associated with Vitamin D receptor mRNA instability in HC11 mammary cells

“…values are presented. HC11 (C) vs. HC11 ras (C): p = 0.037; HC11 (C) vs. HC11 ras (F): p = 0.037; HC11 ras (C) vs. HC11 ras (F): p = 0.037. could downregulate the transcription of some genes, such as LUCA15, a tumor suppressor gene [24] and clusterin, an extracellular glycoprotein involved in apoptosis [25] in Rat 1 fibroblasts, as well as Wnt5a and Wnt7a, genes involved in tumor growth and cell adhesion regulation, in a normal spontaneously immortalized human mammary epithelial cell line, MCF-10A [26]. In a previous work, we have reported that NIH3T3 ras transformed fibroblasts displayed lower glucocorticoid receptor (GR) citoplasmatic levels [27] in part caused by a reduced transcription of the GR gene [28], which seemed to be associated with H-ras cellular transformation.…”

Matrix-mediated canal formation in primmorphs from the sponge Suberites domuncula involves the expression of a CD36 receptor-ligand system

“…Four permanent mammalian tumor cell lines were applied to determine the cytotoxic effect caused by MTN: murine leukemic lymphoblasts L5178y (ATCC CRL 1722), rat adrenal pheochromocytoma cells PC-12 (ATCC CRL 1721), human cervix HeLa S3 cells (ATCC CCL 2.2) and the rat embryonal fibroblast cells Rat1 (Klock et al, 1998). The tumor cells were grown as described previously (Müller et al, 1977;Bartl et al, 2001) with the modification that RPMI 1640 medium, enriched with 10% fetal calf serum was used.…”

Induction of Host Gene Expression following Infection of Chicken Embryo Fibroblasts with Oncogenic Marek's Disease Virus

“…Clusterin is a conserved glycoprotein, also known as apolipoprotein J, whose expression is increased in many cell types in response to stress. Clusterin has been reported to have chaperonin-like activity (22) and anti-inflammatory activity (32), and it is expressed during tissue differentiation and remodeling involving apoptosis (26,29).…”