Downregulation of ERK2 is essential for the inhibition of radiation-induced cell death in HSP25 overexpressed L929 cells

Hn, Cho; Yj, Lee; Ck, Cho; Sj, Lee; Ys, Lee

doi:10.1038/sj.cdd.4400979

Cited by 22 publications

(19 citation statements)

References 27 publications

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“…Surprisingly, this effect was associated with prolonged inhibition of baseline Erk phosphorylation, in particular Erk2. The differential involvement of Erk2 in apoptotic processes has been reported previously in several cell types, including macrophages, which have the same ontogeny as osteoclasts (37)(38)(39). Importantly, the opposing effects of OS on osteoblast and osteoclast Erk indicate that as in the case of the CB 2 cannabinoid receptor (11), signaling by the putative OS receptor is cell-type dependent.…”

Section: Discussionmentioning

confidence: 90%

Oleoyl serine, an endogenous N -acyl amide, modulates bone remodeling and mass

Smoum

Bar²,

Tan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Bone mass is determined by a continuous remodeling process, whereby the mineralized matrix is being removed by osteoclasts and subsequently replaced with newly formed bone tissue produced by osteoblasts. Here we report the presence of endogenous amides of long-chain fatty acids with amino acids or with ethanolamine (N-acyl amides) in mouse bone. Of these compounds, N-oleoyl-L-serine (OS) had the highest activity in an osteoblast proliferation assay. In these cells, OS triggers a Gi-protein-coupled receptor and Erk1/2. It also mitigates osteoclast number by promoting osteoclast apoptosis through the inhibition of Erk1/2 phosphorylation and receptor activator of nuclear-κB ligand (RANKL) expression in bone marrow stromal cells and osteoblasts. In intact mice, OS moderately increases bone volume density mainly by inhibiting bone resorption. However, in a mouse ovariectomy (OVX) model for osteoporosis, OS effectively rescues bone loss by increasing bone formation and markedly restraining bone resorption. The differential effect of exogenous OS in the OVX vs. intact animals is apparently a result of an OVX-induced decrease in skeletal OS levels. These data show that OS is a previously unexplored lipid regulator of bone remodeling. It represents a lead to antiosteoporotic drug discovery, advantageous to currently available therapies, which are essentially either proformative or antiresorptive.fatty acyl amides I n mammals, including humans, bone mass is determined by an unremitting remodeling process whereby the mineralized matrix is continuously removed by osteoclasts and subsequently replaced with newly formed bone tissue produced by osteoblasts. This process is regulated by autocrine/paracrine factors, such as receptor activator of nuclear-κB ligand (RANKL), osteoprotegerin (OPG), bone morphogenetic proteins, and Wnt, as well as circulating hormones (e.g., sex steroids, parathyroid hormone) and brain-derived signals (e.g., sympathetic, pituitary) (1-3). Imbalanced bone remodeling leads to skeletal pathologies, mainly osteoporosis, the most common degenerative disorder in affluent societies, which results from a net increase in bone resorption (4). Identification of endogenous constituents, which regulate bone remodeling and skeletal mass, contributes to the elucidation of the mechanisms involved in this process and offers promise for developing novel antiosteoporotic pharmacotherapy.Amides of long-chain fatty acids with amino acids or with ethanolamine (N-acyl amides) represent a major group of endogenous lipids. In mammalian tissues they have numerous physiological functions. For example, anandamide (arachidonoyl ethanolamide) is the first identified endogenous psychoactive ligand of cannabinoid receptors (5); arachidonoyl serine is an endogenous vasodilator, which does not bind to the cannabinoid receptors (6); and oleoyl ethanolamide is an endogenous structural analog to anandamide that regulates food intake through the activation of GPR 119 (7, 8). The well-established biosynthetic tendency to follow existing p...

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Section: Discussionmentioning

confidence: 90%

Oleoyl serine, an endogenous N -acyl amide, modulates bone remodeling and mass

Smoum

Bar²,

Tan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…6). There have so far been few reports addressing the influence of HSP27 on the ERK activation, except for the study by Lee and co-workers (29,30) where the overexpression of HSP25, the same species as human HSP27 in the mouse, was shown to down-regulate ERK expression, while also inhibiting their activation in mouse fibroblast L929 cells by a reduction in reactive oxygen species. Contrary to our results, HSP25 overexpression attenuated the H 2 O 2 -ERK pathway-mediated apoptosis in their experiments.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylated Heat Shock Protein 27 Represses Growth of Hepatocellular Carcinoma via Inhibition of Extracellular Signal-regulated Kinase

Matsushima‐Nishiwaki

Takai

Adachi

et al. 2008

Journal of Biological Chemistry

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Heat shock protein 27, one of the low molecular weight stress proteins, is recognized as a molecular chaperone; however, other functions have not yet been well established. Phosphorylated heat shock protein 27 levels inversely correlate with the progression of human hepatocellular carcinoma. This study shows that phosphorylated heat shock protein 27 interferes with cell growth of the hepatocellular carcinoma-derived HuH7 cells in the presence of the proinflammatory cytokine, tumor necrosis factor-␣, via inhibition of the sustained activation of the extracellular signal-regulated kinase signal pathway. The activities of Raf/extracellular signal-regulated kinase and subsequent activator protein-1 transactivation and the induction levels of cyclin D1 were lower in HuH7 cells transfected with phosphorylated heat shock protein 27 than those with unphosphorylated heat shock protein 27. Moreover, phosphorylated heat shock protein 27 up-regulated the levels of p38 mitogen-activated protein kinase and mitogen-activated protein kinase phosphatase-1, an inhibitory protein of extracellular signal-regulated kinase. These results indicate that phosphorylated heat shock protein 27 might suppress the extracellular signal-regulated kinase activity in the hepatocellular carcinoma cells via two separate pathways in an inflammatory state. The extracellular signal-regulated kinase activity is inversely correlated with phosphorylated heat shock protein 27 at serine 15 and also in human hepatocellular carcinoma tissues in vivo. Because the extracellular signal-regulated kinase signal pathway is a major proliferation signal of hepatocellular carcinoma, activator protein-1 activation is an early event in hepatocarcinogenesis. These findings strongly suggest that the control of the phosphorylated heat shock protein 27 levels could be a new therapeutic strategy especially to counter the recurrence of hepatocellular carcinoma.The mammalian small stress protein, heat shock protein (HSP) 2 27, is a widely expressed 27-kDa protein, and it is one of 10 members of the human low molecular weight HSP family. HSPs are classified into high molecular weight HSPs such as HSP70 and HSP90, and low molecular weight HSPs with molecular masses from 10 to 30 kDa based on their apparent molecular sizes. Low molecular weight HSPs have significant similarities in terms of amino acid sequences, known as the ␣-crystallin domain and WDPF motif (1, 2). The high molecular weight HSPs act as molecular chaperones in protein folding, oligomerization, and translocation (1). Although the functions of low molecular weight HSPs are not as well characterized as those of the high molecular weight HSPs, it is recognized that they may have chaperone activities (1). The functions of HSP27 are regulated by post-translational modifications such as phosphorylation (3, 4). Mouse HSP27 is phosphorylated at two sites (Ser-15 and Ser-82), whereas human HSP27 is phosphorylated at three sites (Ser-15, Ser-78, and Ser-82) (3). Ser-78 and Ser-82 of HSP27 are adjacent to the amino-termin...

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“…Reduction of radiation-mediated apoptosis in HSP25 overexpressing cells HSP25 has been shown to induce resistance to radiation and TNF-mediated oxidative stress in L929 cells (Susin et al, 1999;Cho et al, 2002). Therefore, a possible relationship between HSP25 and resistance to DNA fragmentations was examined.…”

Section: Resultsmentioning

confidence: 99%

“…Small heat shock protein (sHSP) has been suggested to protect cells against apoptotic cell death, triggered by a variety of stimuli, including hyperthermia, ionizing radiation, oxidative stress, Fas ligand and cytotoxic drugs (Huot et al, 1991;Oesterreich et al, 1993;Garrido et al, 1996;Park et al, 2000;Cho et al, 2002). We earlier reported that radioprotecting effect of HSP25 was to delay cell growth, which was likely mediated by inhibition of cyclin D1, A, and Cdc2 expressions, and increase of Bcl-2 expression (Park et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

HSP25 inhibits radiation-induced apoptosis through reduction of PKCδ-mediated ROS production

Lee

Cho

et al. 2005

Oncogene

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Since radiation-induced caspase-dependent apoptosis and ROS generation were partially prevented by HSP25 overexpression, similar to the treatment of control cells with antioxidant agents such as DPI and tiron, questions arise whether radiation-mediated ROS generation contributes to the apoptotic cell death, and also whether HSP25 overexpression can reduce ROS mediated apoptotic cell death. In the present study, radiation-induced cytochrome c release from mitochondria and activation of caspases accompanied by a decrease of mitochondrial membrane potential in Jurkat T cells were shown to be inhibited by mitochondrial complex I inhibitor rotenone, suggesting that mitochondrial ROS might be important in radiation-induced caspase-dependent apoptosis. When HSP25 was overexpressed, effects similar to the treatment of cells with the antioxidants were obtained, indicating that HSP25 suppressed radiation-induced mitochondrial alteration that resulted in apoptosis. Furthermore, activation of p38 MAP kinase by radiation was associated with radiation-induced cell death and ROS production and PKCd was an upstream molecule for p38 MAP kinase activation, ROS generation and subsequent caspase-dependent apoptotic events. However, in the HSP25 overexpressed cells, the above-described effects were blocked. In fact, radiation-induced membrane translocation of PKCd and tyrosine phosphorylation were inhibited by HSP25. Based on the above data, we suggest that HSP25 downregulates PKCd, which is a key molecule for radiation-induced ROS generation and mitochondrial-mediated caspase-dependent apoptotic events.

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Downregulation of ERK2 is essential for the inhibition of radiation-induced cell death in HSP25 overexpressed L929 cells

Cited by 22 publications

References 27 publications

Oleoyl serine, an endogenous N -acyl amide, modulates bone remodeling and mass

Oleoyl serine, an endogenous N -acyl amide, modulates bone remodeling and mass

Phosphorylated Heat Shock Protein 27 Represses Growth of Hepatocellular Carcinoma via Inhibition of Extracellular Signal-regulated Kinase

HSP25 inhibits radiation-induced apoptosis through reduction of PKCδ-mediated ROS production

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