Abstract
The c-myc gene has been implicated in multiple cellular processes including proliferation, differentiation, and apoptosis. In addition to the full-length c-Myc 1 and 2 proteins, we have found that human, murine, and avian cells express smaller c-Myc proteins arising from translational initiation at conserved downstream AUG codons. These c-Myc short (c-Myc S) proteins lack most of the N-terminal transactivation domain but retain the C-terminal protein dimerization and DNA binding domains. As with full-length c-Myc proteins, the c-Myc S proteins appear to be localized to the nucleus, are relatively unstable, and are phosphorylated. Significant levels of c-Myc S, often approaching the levels of full-length c-Myc, are transiently observed during the rapid growth phase of several different types of cells. Optimization of the upstream initiation codons resulted in greatly reduced synthesis of the c-Myc S proteins, suggesting that a "leaky scanning" mechanism leads to the translation of these proteins. In some hematopoietic tumor cell lines having altered c-myc genes, the c-Myc S proteins are constitutively expressed at levels equivalent to that of full-length c-Myc. As predicted, the c-Myc S proteins are unable to activate transcription and inhibited transactivation by full-length c-Myc proteins, suggesting a dominant-negative inhibitory function. While these transcriptional inhibitors would not be expected to function as full-length c-Myc, the occurrence of tumors which express constitutive high levels of c-Myc S and their transient synthesis during rapid cell growth suggest that these proteins do not interfere with the growth-promoting functions of full-length c-Myc.
Highlights
Increasing evidence suggests that members of the myc family of proto-oncogenes function as regulators of gene transcription and perform a fundamental role in the control of cell growth and differentiation [25, 36, 46]
In a manner reminiscent of observations made with Burkitt’s lymphomas and other neoplastic cells, we observed that most of the bursal lymphoma cell lines did not express the typical pattern of c-Myc proteins as seen with MSB-1 cells having no alterations of the c-myc locus
In addition to the two major full-length forms of c-Myc protein, we and other investigators have previously reported the detection of smaller c-Myc-related proteins in immunoprecipitations from [35S]methionine-labeled cellular lysates or in Western blot analyses [21, 22, 35, 40, 49]. We demonstrate that these smaller proteins in mammalian and avian cells are alternatively initiated forms of c-Myc, termed c-Myc short (c-Myc S) proteins
Summary
Increasing evidence suggests that members of the myc family of proto-oncogenes function as regulators of gene transcription and perform a fundamental role in the control of cell growth and differentiation [25, 36, 46]. 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 [48]. In cells having intact c-myc genes, the alternative translational initiation of c-Myc can be regulated during cell growth. Overexpression of c-Myc 1, unlike that of c-Myc 2, inhibits the growth of COS cells [20]
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