Activation of the Myc oncoprotein leads to increased turnover of thrombospondin-1 mRNA

Abstract

The Myc oncoprotein is implicated in transcriptional regulation of a variety of genes pertaining to cell cycle and neoplastic transformation. Examples of both positive and negative regulation have been reported that involve E-box and initiator (Inr) promoter elements, respectively. In both cases, Myc is thought to induce changes in transcription initiation. We have previously shown that overexpression of Myc causes down-regulation of the thrombospondin-1 (tsp-1) gene, an important negative modulator of tumor angiogenesis. In this study, we demonstrate that Myc in combination with Max can bind, albeit with low affinity, to an E-box-like element in the tsp-1 promoter. However, the 2.7 kb DNA segment containing both this non-canonical E-box and an Inr-like sequence does not constitute a Myc-responsive element in a transient expression system. Furthermore, Myc does not significantly affect the rate of initiation or elongation of the tsp-1 mRNA. Thus, in this instance Myc does not act as a canonical transcription factor. Instead, as demonstrated by blocking de novo RNA synthesis, down-regulation of the tsp-1 gene by Myc occurs through increased mRNA turnover. To our knowledge, this is the first example of gene regulation by Myc that involves mRNA destabilization.

Thrombospondin‐1 as an endogenous inhibitor of angiogenesis and tumor growth

“…This conclusion is consistent with the presence of sites for endonuclease cleavage in the approximately 2kb of untranslated sequence in the 3' end of the TSP-1 message. It is possible that the increase in TSP-1 mRNA turnover results from an increase in the stability or level of expression of an endonuclease that is continuously synthesized because treatment of cells with cycloheximide results in an increase in the level of TSP-1 mRNA [55][56][57].…”

CDK2 Is Required By MYC to Induce Apoptosis

“…[1][2][3][4] MYC overexpression causes tumorigenesis by inducing autonomous and unrestrained cellular proliferation and growth, cellular immortalization, genomic destabilization, blocked cellular differentiation, inappropriate angiogenesis and abnormal cellular adhesion. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] MYC overexpression is restrained from causing tumorigenesis by at least two different molecular mechanisms. Under some circumstances, MYC activation induces apoptosis which serves as a barrier to otherwise unchecked cellular proliferation.…”

Molecular Pathways: Comparing the Effects of Drugs and T Cells to Effectively Target Oncogenes

“…Tumor regression by MYC inactivation in experimental models was accompanied by regression of blood vessels, compatible with the activity of MYC to repress the angiogenesis inhibitor thrombospondin-1 and induce VEGF (25,(33)(34)(35). Reduced numbers of endothelial cells were also found within RAS-deprived melanomas (11) and TagLuc-deprived sarcomas (9), even though in the latter model most endothelial cells persisted in regressing tumors.…”