mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype

By Nicolás Herranz, S. Gallage, M. Mellone, T. Wuestefeld, S. Klotz, Christopher J Hanley, S. Raguz, J. Acosta, A. Innes, Ana Banito and 15 more. Nature Cell Biology, 2015

708 citations recorded by the source corpus.

Senescent cells secrete a combination of factors collectively known as the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence and activates an immune surveillance response, but it can also show pro-tumorigenic properties and contribute to age-related pathologies. In a drug screen to find new SASP regulators, we uncovered the mTOR inhibitor rapamycin as a potent SASP suppressor. Here we report a mechanism by which mTOR controls the SASP by differentially regulating the translation of the MK2 (also known as MAPKAPK2) kinase through 4EBP1. In turn, MAPKAPK2 phosphorylates the RNA-binding protein ZFP36L1 during senescence, inhibiting its ability to degrade the transcripts of numerous SASP components. Consequently, mTOR inhibition or constitutive activation of ZFP36L1 impairs the non-cell-autonomous effects of senescent cells in both tumour-suppressive and tumour-promoting contexts. Altogether, our results place regulation of the SASP as a key mechanism by which mTOR could influence cancer, age-related diseases and immune responses.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/e5c6b05dd1b15397beb7118765439b028758f8ce

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Jesús Gil
2. Alejandra Hernandez-Segura
3. J. Nehme
4. P. Jat
5. A. Alimonti
6. J. Kohli
7. E. Zagato
8. L. Pellegrini

In Physiology

1. P. Jat
2. R. Kumari
3. Jesús Gil
4. Alejandra Hernandez-Segura
5. J. Nehme
6. Nicolás Herranz
7. A. Alimonti
8. J. Kohli

Citations in the corpus

• Senescence and the SASP: many therapeutic avenues (2020, background): “…also promotes the translation of IL-1α and NF-κB activation (Laberge et al. 2015). mTOR regulates the translation of MAPKAPK2, a kinase downstream from p38, which phosphorylates and inhibits the RNA-binding protein ZFP36L1 during senescence, stabilizing SASP mRNA transcripts (Herranz et al. 2015).”
• Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL (2016, neutral): “In contrast to these cells, oncogene-induced senescent cells have increased mTOR signalling leading to an increase in global translation 40,41 .”
• Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “Although mTOR inhibition prevented the protumorigenic effects of the SASP in vivo, it also interfered with the induction of paracrine senescence and senescence surveillance, two important tumor suppressive arms of senescence (158).”
• Mechanisms and functions of cellular senescence. (2018, positive): “It has been described that mTOR-mediated phosphorylation of the translation repressor protein 4EBP regulates the translation of IL-1 α (91) and MAP kinase–activated protein kinase 2 (MAPKAPK2) (92) to control the SASP.”
• Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021, background): “…pathways such as p38MAPK (Freund et al., 2011), JAK2/STAT3 (Hubackova et al., 2010; Xu et al., 2015b), inflammasome (Acosta et al., 2013), mTOR (Herranz et al., 2015; Laberge et al., 2015), phosphoinositide-3-kinase (PI3K) pathway (Bent et al., 2016; Zhang et al., 2018), HSP90 (Di Martino et…”
• Hallmarks of Cellular Senescence. (2018, positive): “However, despite much evidence for the upregulation of mTOR during senescence [66,67,97], the autophagy status of senescent cells is less understood [98].”