Kinases: positive and negative regulators of apoptosis

Franklin, Richard A.; McCubrey, James A.

doi:10.1038/sj.leu.2401967

Cited by 134 publications

(83 citation statements)

References 265 publications

(302 reference statements)

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“…27,28 Therefore, to determine which kinase was actually required for ZBP-89-mediated apoptosis, specific inhibitors and dominant-negative constructs were used to block kinase activation. Cleaved caspase-3 and PARP were determined by immunoblot to assess whether the kinase inhibitors also blocked apoptosis.…”

Section: Inhibition Of Erk Activation Potentiates Zbp-89-induced Apopmentioning

confidence: 99%

ZBP-89-induced apoptosis is p53-independent and requires JNK

et al. 2004

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ZBP-89 induces apoptosis in human gastrointestinal cancer cells through a p53-independent mechanism. To understand the apoptotic pathway regulated by ZBP-89, we identified downstream signal transduction targets. Ectopic expression of ZBP-89 induced apoptosis through the mitochondrial pathway and was accompanied by activation of all three MAP kinase subfamilies: JNK1/2, ERK1/2 and p38 MAP kinase. ZBP-89-induced apoptosis was markedly enhanced by ERK inhibition with U0126. In contrast, inhibiting JNK with a JNK1-specific peptide inhibitor or dominant-negative JNK2 expression abrogated ZBP-89-mediated apoptosis. The p38 inhibitor SB202190 had no effect on ZBP-89-induced cell death. Protein dephosphorylation assays revealed that ZBP-89 activates JNK via repression of JNK dephosphorylation. Oligonucleotide microarray analyses revealed that ectopic expression of ZBP-89 downregulated expression of the dual-specificity phosphatase MKP6. Overexpression of MKP6 blocked ZBP-89-induced JNK phosphorylation and PARP cleavage. In addition, ectopic expression of ZBP-89 repressed Bcl-xL and Mcl-1 expression, but had no effect on Bcl-2. Silencing ZBP-89 with small interfering RNA enhanced both Bcl-xL and Mcl-1 expression. Taken together, ZBP-89-mediated apoptosis occurs via a p53-independent mechanism that requires JNK activation.

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Section: Inhibition Of Erk Activation Potentiates Zbp-89-induced Apopmentioning

confidence: 99%

ZBP-89-induced apoptosis is p53-independent and requires JNK

et al. 2004

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“…The regulation of apoptosis by signal transduction pathways is complex. 104 Many of the protein kinases and protein phosphatases that participate in these various processes are probably influenced by ceramide, either directly or indirectly. 100 In addition, other signal pathways regulating Bcl2 and other Bcl2 family members are probably regulated by ceramide.…”

Section: Figurementioning

confidence: 99%

Ceramide regulates cellular homeostasis via diverse stress signaling pathways

2001

Leukemia

165

111

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The sphingolipid ceramide is an important second signal molecule that regulates diverse signaling pathways involving apoptosis, cell senescence, the cell cycle, and differentiation. For the most part, ceramide's effects are antagonistic to growth and survival. Interestingly, ceramide and the pro-growth agonist, diacylglycerol (DAG) appear to be regulated simultaneously but in opposite directions in the sphingomyelin cycle. While ceramide stimulates signal transduction pathways that are associated with cell death or at least are inhibitory to cell growth (eg stress-activated protein kinase, SAPK, pathways), DAG activates the classical and novel isoforms of the protein kinase C (PKC) family. These PKC isoforms are associated with cell growth and cell survival.

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“…The reversible phosphorylation and dephosphorylation at the serine and threonine residues on proteins play important roles in regulating gene expression (Hunter and Karin, 1992), cell cycle progression (Pawson, 1995), and apoptosis (Gjertsen and Doskeland, 1995;Franklin and McCubrey, 2000;Klumpp and Krieglstein, 2002). In eukaryotes, dephosphorylation at the serine/ threonine sites is largely executed by four major protein phosphatases: phosphatase-1 (PP-1), phosphatase-2A (PP-2A), phosphatase-2B (PP-2B) and phosphatase-2C (PP-2C) (Cohen, 1989;Mumby and Walter, 1993), although other protein phosphatases, including phosphatase-4 (PP-4), phosphatase-5 (PP-5), phosphatase-6 (PP-6) and phosphatase-7 (PP-7), also contribute to this process (Brewis et al, 1993;Bastians and Ponstingl, 1994;Chen et al, 1994;Chinkers, 1994;Huang and Honkananen, 1998).…”

Section: Introductionmentioning

confidence: 99%

Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities

et al. 2006

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We have previously demonstrated that the serine/threonine protein phosphatase-1 (PP-1) plays an important role in promoting cell survival. However, the molecular mechanisms by which PP-1 promotes survival remain largely unknown. In the present study, we provide evidence to show that PP-1 can directly dephosphorylate a master regulator of apoptosis, p53, to negatively modulate its transcriptional and apoptotic activities, and thus to promote cell survival. As a transcriptional factor, the function of p53 can be greatly regulated by phosphorylation and dephosphorylation. While the kinases responsible for phosphorylation of the 17 serine/threonine sites have been identified, the dephosphorylation of these sites remains largely unknown. In the present study, we demonstrate that PP-1 can dephosphorylate p53 at Ser-15 and Ser-37 through co-immunoprecipitation, in vitro and in vivo dephosphorylation assays, overexpression and silence of the gene encoding the catalytic subunit for PP-1. We further show that mutations mimicking constitutive dephosphorylation or phosphorylation of p53 at these sites attenuate or enhance its transcriptional activity, respectively. As a result of the changed p53 activity, expression of the downstream apoptosis-related genes such as bcl-2 and bax is accordingly altered and the apoptotic events are either largely abrogated or enhanced. Thus, our results demonstrate that PP-1 directly dephosphorylates p53, and dephosphorylation of p53 has as important impact on its functions as phosphorylation does. In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.

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Kinases: positive and negative regulators of apoptosis

Cited by 134 publications

References 265 publications

ZBP-89-induced apoptosis is p53-independent and requires JNK

ZBP-89-induced apoptosis is p53-independent and requires JNK

Ceramide regulates cellular homeostasis via diverse stress signaling pathways

Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities

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