A novel function for Myc: inhibition of C/EBP-dependent gene activation.

Abstract

We have investigated the effect of the v-Myc oncoprotein on gene expression in myelomonocytic cells. We find that v-Myc dramatically down-regulates the expression of myelomonocytic-specific genes, such as the chicken mim-1 and lysozyme genes, both of which are known targets for C/EBP transcription factors. We present evidence that Myc downregulates these genes by inhibiting the function of C/EBP transcription factors. Detailed examination of the inhibitory mechanism shows that amino-terminal sequences of v-Myc, but not its DNA-binding domain, are required for the suppression of C/EBP-dependent transactivation. Our findings identify a new function for Myc and reveal a novel mechanism by which Myc affects the expression of other genes.Numerous studies have implicated the c-myc gene in a variety of cellular processes, such as proliferation, differentiation, and apoptosis, and have shown that mutant forms of the gene, such as transduced (v-myc) or rearranged myc alleles, are involved in tumorigenesis (1-6). It is now widely believed that c-myc plays a central role in a switch mechanism by which normal cells decide between the alternative fates of proliferation, differentiation, and apoptosis and that deregulation of c-myc causes an imbalance in this switch mechanism, resulting in the development of neoplasia.Structural and functional analyses have identified the c-myc protein product (c-Myc) as a transcription factor. The carboxyl terminus of c-Myc forms a basic region-helix-loop-helixleucine zipper (B-HLH-LZ) DNA-binding domain, heterodimerizes with the Max protein (7), and recognizes the consensus Myc binding site, CACGTG (8-10), whereas the amino terminus of c-Myc functions as a transcriptional activation domain (11)(12)(13)(14). Several genes whose expression is induced by c-Myc have been identified (15)(16)(17)(18)(19)(20). In addition, c-Myc also inhibits gene expression. The C/EBPa gene (21,22) and the adenovirus-2 major late promoter (22, 23) are downregulated by c-Myc. Interestingly, repression of these genes does not depend on Myc-specific DNA-binding sites but is mediated by so-called initiator elements located in the promoters of these genes (22, 23). Thus, increasing evidence suggests that c-Myc affects gene expression by several different mechanisms. Nevertheless, an unambiguous functional relationship to the physiological or malignant activities of myc has not been established for any of the putative target genes identified so far.We have studied the effect of v-Myc on gene expression in myelomonocytic cells. We have found that v-Myc inhibits the expression of several genes, including mim-1 and the lysozyme gene, both of which have been shown to be targets for C/EBP transcription factors (24,25). We have analyzed the mechanism by which Myc down-regulates these genes and have found that amino-terminal sequences of Myc interfere with the function of C/EBP transcription factors. Our findings identify a novel function for Myc and reveal a novel mechanism by which Myc affects the expression of othe...

WS5, a direct target of oncogenic transcription factor Myc, is related to human melanoma glycoprotein genes and has oncogenic potential

“…The analyses clearly revealed association of p110 gagÀmyc with C/EBP proteins in MC29-transformed cells (Figure 5f), confirming and extending previous circumstantial evidence for possible direct interaction between these proteins (Mink et al, 1996;Hartl et al, 2003).…”

“…C/EBPa is a multifunctional transcription factor that is involved in the specification of the differentiated phenotype through gene activation, but was recently also implicated in the acceleration of cell proliferation and activation of metastasis related genes (Heckman et al, 2003;Liu et al, 2004;Wang and Timchenko, 2005). Notably, functional interactions of Myc with the C/EBPb protein have been reported previously (Mink et al, 1996;Hartl et al, 2003).…”

Myc represses the growth arrest gene gadd45

“…Recently, transient transfection reporter assays demonstrate that in 3T3-L1 cells, ectopic Myc expression can abrogate the C/EBPa mediated activation of gadd45 transcription associated with adipocyte di erentiation (Constance et al, 1996). In addition, Mink et al show ectopic v-Myc can suppress the expression of myelomonocytic speci®c genes by inhibiting both the expression and the function of C/ EBPa transcription factors (Mink et al, 1996) C/EBPa is predominantly expressed in di erentiated cells (Birkenmeier et al, 1989), hence the role of C/EBPa in the G0/G1-associated up-regulation, or Mycmediated repression of gadd45 in cycling cells, remains unclear. Indeed, Myc may repress gadd45 directly by interacting with components of the core transcription complex, indirectly in an enhancer-dependent manner or by a yet unknown mechanism of action.…”

Structure and transcriptional regulation of BKJ, a novel AP-1 target gene activated during jun- or fos-induced fibroblast transformation

“…Furthermore, oncogenic transcription factors may directly or indirectly in¯uence the activity of other transcriptional regulators and thereby amplify functional alterations in the complex transcription factor network leading to a profound disturbance of cellular proliferation control (Miao and Curran, 1994;Mink et al, 1996). The deregulation of several AP-1 responsive genes, like those encoding the metalloproteases stromelysin or type I collagenase, Fos-related antigen Fra-1, or ornithine decarboxylase, has been implicated in the c-fos-dependent malignant progression of skin tumors (Saez et al, 1995) or the fos-induced transformation of rat ®broblasts (Miao and Curran, 1994).…”