Research ArticleCell Biology

Increased MKK4 Abundance with Replicative Senescence Is Linked to the Joint Reduction of Multiple MicroRNAs

Sci. Signal.  27 Oct 2009:
Vol. 2, Issue 94, pp. ra69
DOI: 10.1126/scisignal.2000442

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Four on One

Mitotic cells enter a state known as replicative senescence when they cease to divide. Understanding the signaling pathways involved in triggering senescence could identify possible therapeutic targets to counteract declines characteristic of age-related diseases or to induce cells to cease dividing in proliferative disorders, such as cancer. Marasa et al. found that the kinase MKK4 (mitogen-activated protein kinase kinase 4) was increased in abundance in senescent cells. The concerted actions of four microRNAs were required to suppress translation of MKK4 in proliferating cells. In contrast, the abundance of these microRNAs decreased in senescent cells, thereby relieving the repression of MKK4 translation and allowing MKK4 protein to accumulate. Furthermore, interventions that lowered the abundance of all four microRNAs induced a senescent phenotype in proliferating cells. These results provide insight into how several microRNAs work in concert to contribute to cellular senescence.