Tristetraprolin Blocks the Activity of the MYC Oncogene and Prevents Development of Lymphoma

Many types of cancer result from the action of the MYC oncogene, but a recent study found that this effect could be blocked by activation of the tumor-suppressor protein tristetraprolin.

MYC is a very strong proto-oncogene, and it is very often found to be upregulated in many types of cancers. The Myc protein encoded by this gene is a transcription factor that activates expression of a great number of genes through binding on consensus sequences (Enhancer Box sequences (E-boxes)) and recruiting histone acetyltransferases (HATs). It can also act as a transcriptional repressor. By binding Miz-1 transcription factor and displacing the p300 coactivator, it inhibits expression of Miz-1 target genes. Myc is activated upon various mitogenic signals such as Wnt, Shh, and EGF (via the MAPK/ERK pathway). By modifying the expression of its target genes, Myc activation results in numerous biological effects. The protein encoded by MYC has been found to be highly resistant to chemotherapy mainly because it lacks efficient binding sites for drug compounds.

Tristetraprolin (TTP), also known as zinc finger protein 36 homolog (ZFP36), binds to AU (adenylate-uridylate)-rich elements (AREs) in the 3'-untranslated regions (UTRs) of the mRNAs of some cytokines and promotes their degradation. For example, TTP is a component of a negative feedback loop that interferes with TNF-alpha (tumor necrosis factor-alpha) production by destabilizing its mRNA. Mice deficient in TTP develop a complex syndrome of inflammatory diseases.

Investigators at the Scripps Research Institute (Jupiter, FL, USA) worked with cultures of precancerous and malignant Myc-expressing B cells. They reported in the August 3, 2012, edition of the journal Cell that Myc regulated hundreds of ARE-containing genes and select AU binding proteins. Notably, Myc directly suppressed transcription of TTP, an mRNA-destabilizing AU binding protein. This circuit was also operational during B lymphopoiesis and IL7 signaling. TTP suppression was identified as a hallmark of cancers with Myc involvement. Restoration of TTP activity impaired Myc-induced lymphomagenesis and caused cancerous B-cells to return to their normal phenotype.

"Myc regulates the expression of select AU-binding proteins to control the destruction of certain mRNAs," said senior author Dr. John L. Cleveland, professor of cancer biology at the Scripps Research Institute. "Also, our study strongly suggests that other AU-binding proteins may also, in fact, function as tumor suppressors in other cancers. This opens a new therapeutic avenue to exploit for cancers with Myc involvement—including relapsed metastatic tumors and refractory tumors, those that have not responded to treatment."


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