c-Myc Transactivation Domain Research Articles

Methionine deprivation regulates the translation of functionally-distinct c-Myc proteins.

Numerous studies have demonstrated a critical role for the c-myc gene in the control of cellular growth. Alterations of the c-myc gene have been found associated with many different types of tumors in several species, including humans. The increased synthesis of one of the major forms of c-Myc protein, c-Myc 1, upon methionine deprivation provides a link between the regulation of oncogenes and the nutritional status of the cell. While deregulation or overexpression of the other major form, c-Myc 2, has been shown to cause tumorigenesis, the synthesis of c-Myc 1 protein is lost in many tumors. This suggests that the c-Myc 1 protein is necessary to keep the c-Myc 2 protein "in check" and prevent certain cells from becoming tumorigenic. Indeed, we have shown that overproduction of c-Myc 1 can inhibit cell growth. We have also shown that c-Myc 1 and 2 proteins have a differential molecular function in the regulation of transcription through a new binding site of Myc/Max heterodimers. We have also recently identified new translational forms of the c-Myc protein which we term delta-c-Myc. These proteins arise from translational initiation at downstream start sites which yield N-terminally-truncated c-Myc proteins. Since these proteins lack a significant portion of the transactivation domain of c-Myc, they behave as dominant-negative inhibitors of the full-length c-Myc 1 and 2 proteins. The synthesis of delta-c-Myc proteins is also regulated during cell growth and is repressed by methionine deprivation. Therefore, the synthesis of c-Myc 1 and delta-c-Myc proteins are reciprocally regulated by methionine availability. We have also found some tumor cell lines which synthesize high levels of the delta-c-Myc proteins. Taken together, our data suggest that c-Myc function is dependent on the levels of these different translational forms of c-Myc protein which are regulated by the nutritional status of the cell during growth. Numerous reports have demonstrated a fundamental and diverse role for the myc gene in cellular events, including proliferation, differentiation and apoptosis (Cole 1986; Spencer and Groudine 1991; Askew et al. 1991; Evan et al. 1992). This is dramatically illustrated by the frequent occurrence of a variety of tumors in many species having alterations of myc genes and the transduction of c-myc sequences by retroviruses (Spencer and Groudine 1991).4+ Eisenman 1990).(ABSTRACT TRUNCATED AT 400 WORDS)

Interaction of c-Myc with the pRb-related protein p107 results in inhibition of c-Myc-mediated transactivation.

The product of the c-myc proto-oncogene, c-Myc, is a sequence-specific DNA binding protein with an N-terminal transactivation domain and a C-terminal DNA binding domain. Several lines of evidence indicate that c-Myc activity is essential for normal cell cycle progression. Since the abundance of c-Myc during the cell cycle is constant, c-Myc's activity may be regulated at a post-translational level. We have shown previously that the N-terminus of c-Myc can form a specific complex with the product of the retinoblastoma gene, pRb, in vitro. These data suggested a model in which pRb, or pRb-related proteins, regulate c-Myc activity through direct binding. We show here that the pRb-related protein p107, but not pRb itself, forms a specific complex with the N-terminal transactivation domain of c-Myc in vivo. Binding of p107 to c-Myc causes a significant inhibition of c-Myc transactivation. Expression of c-Myc releases cells from a p107-induced growth arrest, but not from pRb-induced growth arrest. Our data suggest that p107 can control c-Myc activity through direct binding to the transactivation domain and that c-Myc is a target for p107-mediated growth suppression.

Cell cycle regulation of the c-Myc transcriptional activation domain.

The product of the c-myc gene (c-Myc) is a sequence-specific DNA-binding protein that has previously been demonstrated to be required for cell cycle progression. Here we report that the c-Myc DNA binding site confers cell cycle regulation to a reporter gene in Chinese hamster ovary cells. The observed transactivation was biphasic with a small increase in G1 and a marked increase during the S-to-G2/M transition of the cell cycle. This cell cycle regulation of transactivation potential is accounted for, in part, by regulatory phosphorylation of the c-Myc transactivation domain. Together, these data demonstrate that c-Myc may have an important role in the progression of cells through both the G1 and G2 phases of the cell cycle.

Cell Cycle Regulation of the c-Myc Transcriptional Activation Domain

The product of the c-myc gene (c-Myc) is a sequence-specific DNA-binding protein that has previously been demonstrated to be required for cell cycle progression. Here we report that the c-Myc DNA binding site confers cell cycle regulation to a reporter gene in Chinese hamster ovary cells. The observed transactivation was biphasic with a small increase in G1 and a marked increase during the S-to-G2/M transition of the cell cycle. This cell cycle regulation of transactivation potential is accounted for, in part, by regulatory phosphorylation of the c-Myc transactivation domain. Together, these data demonstrate that c-Myc may have an important role in the progression of cells through both the G1 and G2 phases of the cell cycle.

Signal transduction within the nucleus by mitogen-activated protein kinase.

The nucleus is an important target of signal transduction by growth factor receptors that stimulate mitogen-activated protein (MAP) kinases. We tested the hypothesis that MAP kinases have a signaling role within the nucleus by examining the effect of the expression of a human MAP kinase isoform (p41mapk) in tissue culture cells. The expressed p41mapk was found to be localized in both the cytoplasmic and nuclear compartments of the cells. Significantly, the expression of p41mapk caused an increase in the phosphorylation of a nuclear substrate: Ser62 of c-Myc. Phosphorylation at Ser62 stimulated the activity of the NH2-terminal transactivation domain of c-Myc. Thus, p41mapk causes the phosphorylation and regulation of a physiologically significant nuclear target of signal transduction. These data establish that at least one MAP kinase isoform has a nuclear role during signal transduction.