Inactivation of oncogenic cAMP-specific phosphodiesterase 4D by miR-139-5p in response to p53 activation

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Abstract

Increasing evidence highlights the important roles of microRNAs in mediating p53’s tumor suppression functions. Here, we report miR-139-5p as another new p53 microRNA target. p53 induced the transcription of miR-139-5p, which in turn suppressed the protein levels of phosphodiesterase 4D (PDE4D), an oncogenic protein involved in multiple tumor promoting processes. Knockdown of p53 reversed these effects. Also, overexpression of miR-139-5p decreased PDE4D levels and increased cellular cAMP levels, leading to BIM-mediated cell growth arrest. Furthermore, our analysis of human colorectal tumor specimens revealed significant inverse correlation between the expression of miR-139-5p and that of PDE4D. Finally, overexpression of miR-139-5p suppressed the growth of xenograft tumors, accompanied by decrease in PDE4D and increase in BIM. These results demonstrate that p53 inactivates oncogenic PDE4D by inducing the expression of miR-139-5p.The human body is kept mostly free from tumors by the actions of so-called tumor suppressor genes. One such gene encodes a protein called p53, which prevents tumors from growing by regulating the activity of many other genes that either inhibit cell growth or cause cells to die. For example, p53 regulates genes that encode short molecules called microRNAs, which in turn suppress the activity of other target genes.Although a number of microRNAs have been reported as p53-regulated genes, there are still more to find. Discovering these genes would in turn help researchers to better understand exactly how p53 acts to suppress the growth of tumors, and to treat cancers caused by mutations in this tumor suppressor gene.Cao, Wang et al. now discover a new microRNA – called miR-139-5p – as one that is activated by p53 in human cells. Colon tumors produce much lower levels of this microRNA than normal tissues, while the cancer cells with a higher level of miR-139-5p grow slower than do the cancer cells with less miR-139-5p. Further experiments showed that this is because miR-139-5p can suppress the production of a protein called PDE4D, which is often highly expressed in human cancers. The suppression of PDE4D by this microRNA results in an increase in the levels of a protein that can cause cancer cells to die.Cao, Wang et al. suggest that miR-139-5p and PDE4D form part of a signaling pathway that plays an important role in suppressing the growth of colon cancer cells. Since microRNAs often have more than one target, future studies could explore if miR-139-5p regulates the production of other cancer-related proteins as well.

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Cao, B., Wang, K., Liao, J. M., Zhou, X., Liao, P., Zeng, S. X., … Lu, H. (2016). Inactivation of oncogenic cAMP-specific phosphodiesterase 4D by miR-139-5p in response to p53 activation. ELife, 5(2016JULY). https://doi.org/10.7554/eLife.15978

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