Fungal metabolite FR901228 inhibits c-Myc and Fas ligand expression

Abstract

Activation of T lymphocytes often leads to cellular activation, production of cytokines, entry into cell cycle, and expression of Fas (CD95) and Fas ligand (FasL). Although it is well established that the interaction of Fas and FasL results in apoptosis, mechanisms for regulated expression of Fas and FasL are unclear. Our previous work with antisense oligodeoxynucleotides suggested that the protooncogene c-myc is obligatory for activationinduced apoptosis. To study the relationship between cmyc and the Fas/FasL expression, we employed the antisense method and a newly identi®ed fungal metabolite, FR901228, which has been shown to speci®cally inhibit expression of c-myc in ®broblasts. We found that FR901228 could e ectively block activation-induced apoptosis in T cell hybridomas and this was correlated with its speci®c inhibition of c-myc expression. Both FR901228 and antisense oligodeoxynucleotide to c-myc had similar e ect in inhibiting FasL expression. These treatments did not a ect activation-induced production of IL-2, nor the expression of Fas. In addition, FR901228 inhibited the expression of FasL in 3T3 ®broblasts, but not these transfected with c-myc, supporting a speci®c role of c-myc in this process. Thus, c-Myc plays a fundamental role in the regulation of the expression of FasL, but not Fas and IL-2. Our data further de®ned the requirement of c-Myc in activation-induced apoptosis in T cells.

Mechanisms of apoptosis by c-Myc

“…The latter possibility is supported by evidence that transcription of the CD95/Fas ligand is targeted for activation by many apoptotic stimuli, including TCR activation through NF-kB (Kasibhatla et al, 1999), DNA damage and other stresses through NF-kB, the Jnk pathway (AP-1), and Egr-3 (Faris et al, 1998;Kasibhatla et al, 1998;Mittelstadt and Ashwell, 1998). Sensitization by c-Myc in Rat1 ®broblasts was not due to upregulation of CD95/Fas or CD95/Fas ligand, although recent evidence suggests that CD95/ Fas ligand may be a target for activation by c-Myc in other cell types (Wang et al, 1998a). In any case, the biological data indicates that c-Myc can sensitize cells to CD95/Fas ligand by acting at some point downstream of the receptor.…”

“…Third, inhibition of CD95/Fas signaling blocks apoptosis but not proliferation by cMyc in Rat1 ®broblasts (Hueber et al, 1997). CD95/ Fas ligand (CD95L/FasL) may be an additional target of c-Myc in certain cell types (Wang et al, 1998a;D Sakamuro and GC Prendergast, unpublished observations). Lastly, interaction between c-Myc and Bin1 is necessary to activate apoptosis but dispensable to drive proliferation or malignant transformation, in both ®broblast and epithelial cell models (Sakamuro et al, manuscript submitted).…”

“…Ligand binding causes receptor homotrimerization and recruitment on the cytoplasmic face of the membrane of a death-inducing signaling complex (DISC), which includes the adaptors FADD and TRADD and procaspase-8 as crucial physiological death e ectors (Juo et al, 1998;Varfolomeev et al, 1998;Yeh et al, 1998;Zhang et al, 1998). A brief outline of the CD95/ Fas and TNf receptor systems follows since c-Myc has been implied to act both upstream and downstream of each (Janicke et al, 1994;Klefstrom et al, 1994Klefstrom et al, , 1997Hueber et al, 1997;Wang et al, 1998a).…”

Differential Regulation of the Expression of CD95 Ligand, Receptor Activator of Nuclear Factor-κB Ligand (RANKL), TNF-Related Apoptosis-Inducing Ligand (TRAIL), and TNF-α During T Cell Activation

“…Several of these transcription factors have been shown to directly regulate CD95L transcription in response to TCR activation. In addition, we have reported that activation-induced CD95L expression requires the participation of the protooncogene c-myc (31).…”

Deacetylase inhibitors modulate proliferation and self-renewal properties of leukemic stem and progenitor cells

“…Accordingly, AML1/ETO which is present in about 12% of AML cases is ETO-positive hematopoietic cells and, by another group, in various breast cancer cell lines. 34 Downregulation of c-MYC by DACi has been reported previously [35][36][37][38] and may also account for inhibition of LSC capacity. Here, a reduced protein level of c-MYC was recognized as early as 6 h after addition of DACi (data not shown), suggesting that c-MYC repression is a direct effect of DACi treatment.…”