Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells

Jj, Shacka; Ma, Sahawneh; Jd, Gonzalez; Yz, Ye; Tl, D'Alessandro; Ag, Estévez

doi:10.1038/sj.cdd.4401831

Cited by 75 publications

(69 citation statements)

References 40 publications

(65 reference statements)

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“…ONOO Ϫ may release cytochrome c to activate caspase (43); then activated caspase processes PKC at 3 aspartate residues (Asp 210 , Asp 222 , and Asp 239 ) and promotes relief of the autoinhibitory state by separating the kinase domain from the pseudosubstrate autoinhibitory sequence (amino acids 116 -122) (26,41,42,51). However, we cannot exclude other possibilities.…”

Section: Discussionmentioning

confidence: 97%

Protein Kinase Cζ-dependent LKB1 Serine 428 Phosphorylation Increases LKB1 Nucleus Export and Apoptosis in Endothelial Cells

Song

Xie

et al. 2008

Journal of Biological Chemistry

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LKB1 is a serine-threonine protein kinase that, when inhibited, may result in unregulated cell growth and tumor formation. However, how LKB1 is regulated remains poorly understood. The aim of the present study was to define the upstream signaling events responsible for peroxynitrite ( LKB1 is a serine-threonine protein kinase of the calcium calmodulin family, and LKB1 mRNA is ubiquitously expressed in all tissues including liver, skeletal muscle, and cardiac tissue (1, 2). In humans, loss-of-function mutations of LKB1 are associated with the development of a gastrointestinal disorder called Peutz-Jehgers syndrome (3). LKB1 has also been shown to play a role in the formation of sporadic tumors of the lung (4, 5). Therefore, LKB1 is thought to function as a tumor suppressor, with inhibition of LKB1 activity precipitating unregulated cell growth and tumor formation. In support of this tumor suppressor role, LKB1 has been shown to regulate growth and survival processes in several tumor cell lines. For example, reintroduction of LKB1 to LKB1-deficient tumor cells suppresses growth by inducing G 1 arrest (5, 6). In addition, overexpression of LKB1 in a breast cancer cell line reduces cell migration and tumor genesis when injected into an animal cancer model (7). LKB1 is required for p53-dependent apoptosis (8). Importantly, LKB1 is thought to function as a tumor suppressor through its ability to negatively regulate the Akt signaling pathway. In this regard, aberrant Akt signaling is widely recognized as a contributor to the growth of many LKB1-deficient tumors (5), as well as to the induction of vascular endothelial growth factor and angiogenesis in these tumors (9). Moreover, LKB1 can interact with the tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome ten) (10), which is considered a key negative regulator of the phosphatidylinositol 3-kinase/ Akt pathway (11).LKB1 signaling is regulated through two main mechanisms: 1) phosphorylation and 2) subcellular localization. LKB1 can be phosphorylated on several residues, and its phosphorylation is thought to play a key role in cell cycle arrest (12), tumor suppression (4), and cell polarity (13,14). In addition, LKB1 activity appears to be regulated by the formation of complexes with STRAD and MO25. In the absence of these proteins, overexpressed LKB1 is localized to the nucleus. On the other hand, formation of the LKB1⅐MO25⅐STRAD complex causes a relocalization of LKB1 to the cytosol (a major site of LKB1 action) and enhances LKB1 activity (15). The activation of LKB1 by these pseudokinases may regulate signaling pathways downstream of LKB1, including AMP-activated protein kinase and Akt pathways. However, the site(s) of LKB1 phosphorylation and the enzymes upstream of LKB1 remain enigmatic.We have previously shown that high glucose increases endothelial apoptosis by LKB1-dependent PTEN-mediated Akt inhibition (16). In endothelial cells, LKB1 activates AMP-activated protein kinase in response to reactive nitrogen species or metformin through a pro...

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Section: Discussionmentioning

confidence: 97%

Protein Kinase Cζ-dependent LKB1 Serine 428 Phosphorylation Increases LKB1 Nucleus Export and Apoptosis in Endothelial Cells

Song

Xie

et al. 2008

Journal of Biological Chemistry

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“…For instance, either exogenously administered or endogenously produced RNS were capable of activating JNK and inducing apoptosis in various cell types. 26 Therefore, data from our study expand the functional scope of JNK in response to RNS and it is likely that JNK is involved in both types of cell death elicited by RNS. The effect of RNS on JNK has been found to be doubleedged: RNS may activate or inhibit JNK depending on the exposure condition and cell type.…”

Section: Discussionsupporting

confidence: 52%

Signaling pathways from membrane lipid rafts to JNK1 activation in reactive nitrogen species-induced non-apoptotic cell death

Zhang

et al. 2007

Cell Death Differ

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At present, the signaling pathways controlling reactive nitrogen species (RNS)-induced non-apoptotic cell death are relatively less understood. In this work, various RNS donors are found to induce caspase-independent non-apoptotic cell death in mouse embryonic fibroblasts (MEF). In search of the molecular mechanisms, we first established the role of c-Jun N-terminal kinase (JNK) in RNS-induced non-apoptotic cell death. RNS readily activate JNK, and the jnk1À/À MEF are resistant to RNS-induced cell death. Moreover, the reconstitution of JNK1 effectively restores the sensitivity to RNS. Next, we identified tumor necrosis factor receptor-associated factor 2 (TRAF2) and apoptosis signal-regulating kinase 1 (ASK1) as the essential upstream molecules for RNS-induced JNK activation and cell death. RNS fail to activate JNK and induce cell death in traf2À/À MEF; and reconstitution of TRAF2 effectively restores the responsiveness of traf2À/À MEF to RNS. Moreover, RNS-induced ASK1 activation is impaired in traf2À/À cells and overexpression of a mutant ASK1 protein suppresses RNS-induced cell death in wild-type MEF cells. Last, we explored the signaling events upstream of TRAF2 and found that translocation of TRAF2 and JNK1 onto membrane lipid rafts is required for RNS-mediated JNK1 activation and cell death. Taken together, data from our study reveal a novel signaling pathway regulating RNS-induced JNK1 activation and non-apoptotic cell death.

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“…21 Peroxynitrite is known to induce cell death in various cell types, such as apoptosis of epithelial cells, macrophages, neuronal cell line PC12, and endothelial cells. 21,37,38 Interestingly, peroxynitrite, in contrast to H 2 O 2 , did not induce apoptosis of smooth muscle cells to significant extent in the current study. Peroxynitrite interacts with amino acids, such as cysteine, methionine, and tyrosine, to produce nitrated proteins that undergo facilitated degradation by proteasome.…”

Section: Discussioncontrasting

confidence: 44%

ROS-mediated downregulation of MYPT1 in smooth muscle cells: a potential mechanism for the aberrant contractility in atherosclerosis

Cheng

Tsai

et al. 2013

Laboratory Investigation

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Reactive oxygen species (ROS) mediates the aberrant contractility in hypertension. Abnormal contractility occurs in atherosclerotic vessels but changes in proteins that regulate contractility remain poorly understood. Myosin phosphatase (MP) activity, which regulates smooth muscle relaxation, is regulated by the phosphorylation of its regulatory subunit, MP targeting subunit 1 (MYPT1). In the present study, we examined the roles of ROS in MP subunit expression both in cultured human aortic smooth muscle cells (HASMCs) and during atherosclerosis progression in apolipoprotein E-knockout (apoE-KO) mice. Furthermore, the effect of decreased MYPT1 on actin cytoskeleton and cell migration activity was assessed in HASMCs. Short hairpin RNA-mediated knockdown of MYPT1 increased stress fibers and attenuated platelet-derived growth factor-induced cell migration in HASMCs. Superoxide anion-inducing agent LY83583 downregulated MYPT1 mRNA and protein levels, but did not affect the phosphorylation of MYPT1 and catalytic subunit of MP, PP1d. The LY83583-induced decrease in MYPT1 was abolished by co-treating with superoxide dismutase or by inhibiting NADPH oxidase with diphenyleneiodonium. Treatment of peroxynitrite, but not hydrogen peroxide (H 2 O 2 ), downregulated MYPT1 protein expression and induced MYPT1 phosphorylation without affecting mRNA levels. Co-treatment with a proteasome inhibitor, MG-132, eliminated peroxynitrite-induced MYPT1 downregulation. In apoE-KO mice, MYPT1 protein, but not mRNA, levels were markedly decreased in 16-week-and 24-week-old mice. Oral estrogen treatment, which was previously shown to decrease aortic ROS levels, upregulated aortic MYPT1 expression. Moreover, reduction in MYPT1 expression correlated with increased aortic sensitivity toward vasoconstrictors. These results suggested that during atherosclerosis progression oxidative stress mediates the downregulation of MYPT1, which may inhibit smooth muscle cell migration and contribute to the aberrant contractility.Laboratory Investigation (2013) 93, 422-433; doi:10.1038/labinvest.2013 published online 18 February 2013 KEYWORDS: atherosclerosis; contractility; myosin phosphatase; reactive oxygen species; smooth muscle At the molecular level, phosphorylation of the 20-kDa myosin light chains (MLC 20 ) is a key determinant for smooth muscle contraction. MLC 20 phosphorylation levels are determined by the activity ratio between myosin light chain kinase (MLCK) and myosin phosphatase (MP). 1 Although MLCK activation depends on cytoplasmic calcium concentration, MP activity is subject to modulation by various signaling molecules. 2 MP is a heterotrimer comprised of a 37-to 38-kDa catalytic subunit (PP1d), a 110-to 130-kDa regulatory subunit (MP targeting subunit 1; MYPT1), and a 20-kDa subunit of unknown function. The phosphorylation of MYPT1 by protein kinases is a major regulatory mechanism for MP that results in either the inhibition or enhancement of MP activity. 3 Small GTPase RhoA and its effecter, Rho-kinase, inhibit MP activity through ...

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Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells

Cited by 75 publications

References 40 publications

Protein Kinase Cζ-dependent LKB1 Serine 428 Phosphorylation Increases LKB1 Nucleus Export and Apoptosis in Endothelial Cells

Protein Kinase Cζ-dependent LKB1 Serine 428 Phosphorylation Increases LKB1 Nucleus Export and Apoptosis in Endothelial Cells

Signaling pathways from membrane lipid rafts to JNK1 activation in reactive nitrogen species-induced non-apoptotic cell death

ROS-mediated downregulation of MYPT1 in smooth muscle cells: a potential mechanism for the aberrant contractility in atherosclerosis

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