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Slt2p phosphorylation induces cyclin C nuclear-to-cytoplasmic translocation in response to oxidative stress.

ABSTRACT: The yeast C-type cyclin represses the transcription of genes required for the stress response and meiosis. To relieve this repression, cyclin C undergoes nuclear-to-cytoplasmic translocation in response to many stressors, including hydrogen peroxide, where it is destroyed by ubiquitin-mediated proteolysis. Before its destruction, cyclin C promotes stress-induced mitochondrial fission and programmed cell death, indicating that relocalization is an important cell fate regulator. Here we show that cyclin C cytoplasmic translocation requires the cell wall integrity (CWI) mitogen-activated protein kinase Slt2p, its pseudokinase paralogue, Kdx1p, and an associating transcription factor, Ask10p. Furthermore, Slt2p and Kdx1p regulate cyclin C stability through different but required mechanisms. Slt2p associates with, and directly phosphorylates, cyclin C at Ser-266. Eliminating or mimicking phosphorylation at this site restricts or enhances cyclin C cytoplasmic translocation and degradation, respectively. Conversely, Kdx1p does not bind cyclin C but instead coimmunoprecipitates with Ask10p, a transcription factor previously identified as a regulator of cyclin C destruction. These results reveal a complex regulatory circuitry involving both downstream effectors of the CWI mitogen-activated protein kinase signal transduction pathway to target the relocalization and consequent destruction of a single transcriptional repressor.

SUBMITTER: Jin C

PROVIDER: S-EPMC3983003 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Slt2p phosphorylation induces cyclin C nuclear-to-cytoplasmic translocation in response to oxidative stress.

Jin Chunyan C Strich Randy R Cooper Katrina F KF

Molecular biology of the cell 20140219 8

The yeast C-type cyclin represses the transcription of genes required for the stress response and meiosis. To relieve this repression, cyclin C undergoes nuclear-to-cytoplasmic translocation in response to many stressors, including hydrogen peroxide, where it is destroyed by ubiquitin-mediated proteolysis. Before its destruction, cyclin C promotes stress-induced mitochondrial fission and programmed cell death, indicating that relocalization is an important cell fate regulator. Here we show that ...[more]

PMID: 24554767

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Project description:BackgroundMembrane-anchored heparin-binding epidermal growth factor-like growth factor (proHB-EGF) yields soluble HB-EGF, which is an epidermal growth factor receptor (EGFR) ligand, and a carboxy-terminal fragment of HB-EGF (HB-EGF-CTF) after ectodomain shedding. We previously reported that HB-EGF-CTF and unshed proHB-EGF which has the cytoplasmic domain of proHB-EGF (HB-EGF-C), translocate from the plasma membrane to the nucleus and regulate cell cycle after shedding stimuli. However, the significance of nuclear exported HB-EGF-C in human gastric cancer is unclear.MethodsWe investigated the relationship between intracellular localization of HB-EGF-C and clinical outcome in 96 gastric cancer patients treated with gastrectomy. Moreover, we established stable gastric cancer cell lines overexpressing wild-type HB-EGF (wt-HB-EGF) and mutated HB-EGF (HB-EGF-mC), which prevented HB-EGF-C nuclear translocation after shedding. Cell motility between these 2 gastric cancer cell lines was investigated using a transwell invasion assay and a wound healing assay.ResultsOf the 96 gastric cancer cases, HB-EGF-C immunoreactivity was detected in both the nucleus and cytoplasm in 19 cases (19.8 %) and in the cytoplasm only in 25 cases (26.0 %). The nuclear immunoreactivity of HB-EGF-C was significantly increased in stage pT3/4 tumors compared with pT1/2 tumors (T1/2 vs. T3/4: 11.1 % vs. 36.4 %, P < 0.01). The growth of wt-HB-EGF- and HB-EGF-mC-expressing cells significantly increased compared with control cells, but the growth of HB-EGF-mC-expressing cells was significantly decreased compared with wt-HB-EGF-expressing cells. Gastric cancer cell invasion obviously increased in wt-HB-EGF-expressing cells, but invasion in HB-EGF-mC-expressing cells showed a slight increase compared with control cells. Moreover, wt-HB-EGF overexpression increased the effectiveness of wound healing, but had no significant effect in HB-EGF-mC-expressing cells.ConclusionsBoth the function of HB-EGF as an EGFR ligand and a novel signal for HB-EGF-C nuclear translocation induce gastric cancer growth, whereas HB-EGF-C nuclear translocation independently plays a critical role in gastric cancer invasion. The present study demonstrated that HB-EGF-C nuclear translocation might be crucial in gastric cancer invasion. HB-EGF-C nuclear translocation may offer a prognostic marker and a new molecular target for gastric cancer therapy.

Dataset Information

Slt2p phosphorylation induces cyclin C nuclear-to-cytoplasmic translocation in response to oxidative stress.

Publications

Slt2p phosphorylation induces cyclin C nuclear-to-cytoplasmic translocation in response to oxidative stress.

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