Abstract
The HIPPO pathway is an evolutionary conserved regulator of organ size that controls both cell proliferation and death. This pathway has an important role in mediating cell death in response to oxidative stress through the inactivation of Yes-associated protein (YAP) and inhibition of anti-oxidant gene expression. Cells exposed to oxidative stress induce the phosphorylation of the alpha (α) subunit of the translation initiation factor eIF2 at serine 51 (eIF2αP), a modification that leads to the general inhibition of mRNA translation initiation. Under these conditions, increased eIF2αP facilitates the mRNA translation of activating transcription factor 4 (ATF4), which mediates either cell survival and adaptation or cell death under conditions of severe stress. Herein, we demonstrate a functional connection between the HIPPO and eIF2αP-ATF4 pathways under oxidative stress. We demonstrate that ATF4 promotes the stabilization of the large tumor suppressor 1 (LATS1), which inactivates YAP by phosphorylation. ATF4 inhibits the expression of NEDD4.2 and WWP1 mRNAs under pro-oxidant conditions, which encode ubiquitin ligases mediating the proteasomal degradation of LATS1. Increased LATS1 stability is required for the induction of cell death under oxidative stress. Our data reveal a previously unidentified ATF4-dependent pathway in the induction of cell death under oxidative stress via the activation of LATS1 and HIPPO pathway.
Highlights
The HIPPO pathway is conserved from Drosophila to mammals and is involved in cell growth, proliferation, apoptosis, organ size and tumorigenesis [1]
When yes-associated protein (YAP)/ transcriptional co-activator with PDZ-binding motif (TAZ) is not phosphorylated by the LATS kinases, they translocate to the nucleus and bind to sequence specific transcription factors TEAD1-4, which www.impactjournals.com/oncotarget enables the transcription of genes involved in proliferation and survival [3]
We examined large tumor suppressor 1 (LATS1) expression and YAP phosphorylation in primary mouse embryonic fibroblasts as well as primary and immortalized human fibroblasts that were genetically engineered to be impaired in eIF2αP [19]
Summary
The HIPPO pathway is conserved from Drosophila to mammals and is involved in cell growth, proliferation, apoptosis, organ size and tumorigenesis [1]. It consists of two groups of kinases, the mammalian STE20-like protein kinase 1 (MST1) and MST2, and the large tumor suppressor 1 (LATS1) and LATS2, in combination with their activating adaptor proteins, Salvador family WW domain-containing protein 1 (SAV1) and MOB kinase activator 1 (MOB1), respectively [1]. Cells respond to various stress forms by blocking the initiation process via the phosphorylation of eIF2α at serine (S) 51 ( referred to as eIF2αP), a modification that leads to global inhibition of protein synthesis [4, 5]. MRNAs encoding for the activating transcription factor 4 (ATF4) and ATF5 in mammalian cells, or general control non-repressed 4 (GCN4) in yeast, are better translated under conditions of increased eIF2αP through delayed translation re-initiation from upstream open reading frames (uORFs) within the 5’ untranslated region (5’ UTR) [8,9,10]
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