Untitled

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.

Clusterin/apolipoprotein J is a novel biomarker of cellular senescence that does not affect the proliferative capacity of human diploid fibroblasts

“…3A,B, lanes 5, 6). It is worth mentioning that the di¡erence noticed in the Apo J expression levels between the WI-38/SV40 T Ag and the WI-38 primary ¢broblasts is consistent with previous data showing that senescence-induced genes are suppressed in immortalized and/or transformed cells [8,33]. All the obtained Apo J-overexpressing WI-38/SV40 T Ag ApoJ cell lines did not show any di¡erence in cell morphology when compared with the non-transfected WI-38/SV40 T Ag or with the WI-38/SV40 T Ag pcDNA3X1 cells.…”

Oncogenic HRAS suppresses clusterin expression through promoter hypermethylation

“…Upregulation of clusterin leads to suppression of tumorigenesis in concert with the downregulation of HRAS (Kyprianou et al, 1991). In RAS-transformed cell lines, clusterin expression is consistently downregulated (Klock et al, 1998;Tchernitsa et al, 2004). Nevertheless, further experiments are required to investigate the contribution of clusterin suppression to RAS transformation and to investigate whether clusterin silencing is caused by promoter hypermethylation in tumour samples with mutated RAS.…”

Nerve growth factor and epidermal growth factor stimulate clusterin gene expression in PC12 cells

“…Clusterin is synthesized at an elevated level during a number of physiological processes such as development and differentiation, and in various pathological disorders [3,6,7]. Clusterin expression was shown to be correlated with apoptosis (programmed cell death) in a number of systems, where it is expressed not in the dying cells but in the surviving neighbour cells [2,8,9]. Furthermore, clusterin has been identified as an inhibitor of complement lysis [10].…”