Abstract
The death receptor CD95 (APO-1/Fas) mediates apoptosis induction upon ligation by its cognate ligand CD95L. Two types of CD95 signaling pathways have been identified, which are characterized by the absence (Type I) or presence (Type II) of mitochondrial involvement. Micro(mi)RNAs are small noncoding RNAs that negatively regulate gene expression. They are important regulators of differentiation processes and are found frequently deregulated in many human cancers. We recently showed that Type I cells express less of the differentiation marker miRNA let-7 and, hence, likely represent more advanced tumor cells than the let-7 high expressing Type II cells. We have now identified miR-34a as a selective marker for cells that are sensitive to CD95-mediated apoptosis. Both CD95 and miR-34a are p53 target genes, and consequently, both the sensitivity of cancer cells to CD95-mediated apoptosis and the ability to respond to p53 mediated DNA genotoxic stress are linked. Interestingly, while miR-34a was found to positively correlate with the ability of cells to respond to genotoxic stress, let-7 was negatively correlated. The expression level of CD95 inversely correlated with the expression of let-7 suggesting regulation of let-7 expression by CD95. To test a link between p53 and miR-34a, we altered the expression of CD95. This affected the ability of cells to activate p53 and to regulate miR-34a. Our data point to a novel regulatory network comprising p53, CD95, let-7, and miR-34a that affects cancer cell survival, differentiation, and sensitivity to apoptotic signals. The possible relevance of this regulatory network for cancer stem cells is discussed.
Highlights
CD95 (Fas, APO-1, TNFRSF6) is a prototypical member of the TNF-receptor superfamily [1,2]
Our analysis revealed that 22 of the 59 tested cell lines were sensitive to apoptosis upon stimulation of CD95, and that these could be separated into 11 Type I and 11 Type II cell lines
To determine whether there are miRNAs that correlate with the sensitivity of cancer cells to CD95-mediated apoptosis, we interrogated an expression data set of 208 miRNAs determined by real-time PCR from the NCI60 cells used in our previous studies [15,23]
Summary
CD95 (Fas, APO-1, TNFRSF6) is a prototypical member of the TNF-receptor superfamily [1,2]. Like other DRs such as TNF-R1 and TRAIL receptors, CD95 is capable of mediating apoptosis induction in response to binding of its extracellular ligand, CD95L (CD178, FasL, TNFSF6) [3]. The CD95 DD is able to interact and tether the adaptor molecule FADD which recruits caspase-8 leading to the formation of the death inducing signaling complex (DISC) and the activation of caspase-8 [7,8]. In Type I cells such as T lymphocytes ample amounts of active caspase-8 are generated at the DISC for direct cleavage and subsequent activation of effector caspase-3. In Type II cells such as hepatocytes and pancreatic island b-cells, a reduced amount of DISC is formed leading to weak activation of caspase-8. To induce apoptosis in these cells, mitochondrial amplification of the death signal is necessary. Release of mitochondrial proapoptotic factors such as Smac/Diablo and cytochrome c activates
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