A small peptide mimicking the key domain of MEPE/OF45 interacting with CHK1 protects human cells from radiation-induced killing

Yu, Xiaoyan; Wang, Hongyan; Liu, Shuang; Zhang, Xiangming; Guida, Peter; Hu, Baocheng; Wang, Ya

doi:10.4161/cc.9.10.11651

Cited by 3 publications

(2 citation statements)

References 22 publications

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“…After DNA damage, CHK1 is phosphorylated at aa 317 and 345 by ATR, its upstream kinase, which not only activates CHK1 that results in CHK1 autophosphorylation (S296) and phosphorylates its downstream targets, but also stimulates CHK1 degradation through ubiquitin-mediated proteolysis (Zhang et al, 2009; Zhang et al, 2005). We also discovered that CHK1 interacts directly with MEPE (Liu et al, 2009), and the key domain of human MEPE at the C-terminal region (aa 488–507) interacts with CHK1 and protects CHK1 from ubiquitin-mediated proteolysis (Yu et al, 2010; Zhang et al, 2010). Since the key domain where MEPE interacts with CHK1 overlaps with the digestion sites of MEPE by Cathepsin B (Fig.…”

Section: Discussionmentioning

confidence: 98%

Radiation activated CHK1/MEPE pathway may contribute to microgravity-induced bone density loss

Zhang

Wang

2015

Life Sciences in Space Research

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Bone density loss in astronauts on long-term space missions is a chief medical concern. Microgravity in space is the major cause of bone density loss (osteopenia), and it is believed that high linear energy transfer (LET) radiation in space exacerbates microgravity-induced bone density loss; however, the mechanism remains unclear. It is known that acidic serine- and aspartate-rich motif (ASARM) as a small peptide released by matrix extracellular phosphoglycoprotein (MEPE) promotes osteopenia. We previously discovered that MEPE interacted with checkpoint kinase 1 (CHK1) to protect CHK1 from ionizing radiation promoted degradation. In this study, we addressed whether the CHK1-MEPE pathway activated by radiation contributes to the effects of microgravity on bone density loss. We examined the CHK1, MEPE and secreted MEPE/ASARM levels in irradiated (1 Gy of X-ray) and rotated cultured human osteoblast cells. The results showed that radiation activated CHK1, decreased the levels of CHK1 and MEPE in human osteoblast cells and increased the release of MEPE/ASARM. These results suggest that the radiation-activated CHK1/MEPE pathway exacerbates the effects of microgravity on bone density loss, which may provide a novel targeting factor/pathway for a future countermeasure design that could contribute to reducing osteopenia in astronauts.

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Section: Discussionmentioning

confidence: 98%

Radiation activated CHK1/MEPE pathway may contribute to microgravity-induced bone density loss

Zhang

Wang

2015

Life Sciences in Space Research

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“…The distribution of cells in the cell cycle was measured as described before (Yu et al, 2010). The cells were collected after growing in medium with (10% calf serum) or without serum for 12 h. Cells were stained with the solution [62 µg/ml RNase A, 40 µg/ml propidium iodide and 0.1% Triton X‐100 in phosphate‐buffered saline (PBS) buffer] at room temperature for 1 h in a flow cytometer (Beckman Cell Lab Quanta™ SC, Miami, FL).…”

Section: Methodsmentioning

confidence: 99%

The Ku‐dependent non‐homologous end‐joining pathway contributes to low‐dose radiation‐stimulated cell survival

Yu¹,

Wang²,

Wang³

et al. 2010

Journal Cellular Physiology

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Low-dose (≤0.1 Gy) radiation-induced adaptive responses could protect cells from high-challenge dose radiation-induced killing. The protective role is believed to promote the repair of DNA double-strand breaks (DSBs) that are a severe threat to cell survival. However, it remains unclear which repair pathway, homologous recombination repair (HRR) or non-homologous end-joining (NHEJ), is promoted by low-dose radiation. To address this question, we examined the effects of low-dose (0.1 Gy) on high-challenge dose (2–4 Gy) induced killing in NHEJ- or HRR-deficient cell lines. We showed that 0.1 Gy reduced the high-dose radiation-induced killing for wild-type or HRR-deficient cells, but enhanced the killing for NHEJ-deficient cells. Interestingly, low-dose radiation also enhanced the killing for wild-type cells exposed to high-challenge dose radiation with high-linear energy transfer (LET). Because it is known that high-LET radiation induces an inefficient NHEJ, these results support that the low-dose radiation-stimulated protective role in reducing high-challenge dose (low-LET)-induced cell killing might depend on NHEJ. In addition, we showed that low-dose radiation activated the DNA-PK catalytic subunit (DNA-PKcs) and the inhibitor of DNA-PKcs destroyed the low-dose radiation-induced protective role. These results suggest that low-dose radiation might promote NHEJ through the stimulation of DNA-PKcs activity and; therefore, increase the resistance of cells to high-challenge dose radiation-induced killing.

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Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascade Inhibitors: How Mutations Can Result in Therapy Resistance and How to Overcome Resistance

et al. 2012

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The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Targeting these pathways is often complex and can result in pathway activation depending on the presence of upstream mutations (e.g., Raf inhibitors induce Raf activation in cells with wild type (WT) RAF in the presence of mutant, activated RAS) and rapamycin can induce Akt activation. Targeting with inhibitors directed at two constituents of the same pathway or two different signaling pathways may be a more effective approach. This review will first evaluate potential uses of Raf, MEK, PI3K, Akt and mTOR inhibitors that have been investigated in pre-clinical and clinical investigations and then discuss how cancers can become insensitive to various inhibitors and potential strategies to overcome this resistance.

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A small peptide mimicking the key domain of MEPE/OF45 interacting with CHK1 protects human cells from radiation-induced killing

Cited by 3 publications

References 22 publications

Radiation activated CHK1/MEPE pathway may contribute to microgravity-induced bone density loss

Radiation activated CHK1/MEPE pathway may contribute to microgravity-induced bone density loss

The Ku‐dependent non‐homologous end‐joining pathway contributes to low‐dose radiation‐stimulated cell survival

Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascade Inhibitors: How Mutations Can Result in Therapy Resistance and How to Overcome Resistance

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