Regulation of both apoptosis and cell survival by the v-Src oncoprotein

Johnson, D. Gale; Agochiya, Mahima; Samejima, Kumiko; Earnshaw, William C.; Frame, Margaret C.; Wyke, John A.

doi:10.1038/sj.cdd.4400700

Cited by 69 publications

(62 citation statements)

References 62 publications

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“…As mitochondrial depolarization preceded morphological signs of apoptosis, and as bcl-2 (a regulator of the mitochondrial permeability transition pore Hirsch et al, 1997)) inhibited apoptosis, the functional role of mitochondria during apoptosis mediated by glutathione depletion is shown. Apoptosis induction after glutathione depletion was not attenuated through expression of the src oncogene, whereas apoptosis induction by serum withdrawal has been reported to be inhibited by either bcl-2 overexpression or src oncogene expression (Johnson et al, 2000). This finding may be helpful to further dissect the underlying intracellular signaling pathways.…”

Section: Discussionmentioning

confidence: 84%

Proapoptotic and redox state-related signaling of reactive oxygen species generated by transformed fibroblasts

Schimmel¹,

Bauer²

2002

Oncogene

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Oncogenic transformed fibroblasts are characterized by extracellular superoxide anion generation through a membrane-associated NADPH oxidase. After cellular glutathione depletion, extracellular reactive oxygen species (ROS) generated by transformed fibroblasts exhibit a strong apoptosis-inducing potential. As apoptosis induction under glutathione depletion is inhibited by catalase, the NADPH oxidase inhibitor apocynin, superoxide dismutase, the hydroxyl radical scavenger terephthalate and the iron chelator deferoxamine, the metal-catalysed Haber-Weiss reaction seems to be the responsible signaling mechanism. In contrast to extracellular ROS, intracellular ROS play no role for apoptosis induction in glutathione-depleted transformed fibroblasts initially, since a high level of intracellular catalase scavenges intracellular hydrogen peroxide. Intracellular catalase seems to be induced by extracellular hydrogen peroxide, as pretreatment of transformed fibroblasts with exogenous catalase downmodulates endogenous catalase and renders glutathione-depleted transformed cells susceptible for the effect of endogenous hydrogen peroxide. In contrast to transformed fibroblasts, nontransformed glutathione-depleted fibroblasts do not generate substantial extracellular ROS, but apoptosis is efficiently induced in these cells by intracellular ROS. Our data show that extracellular ROS of transformed fibroblasts exhibit redox-related signaling and at the same time represent a potential apoptosis-inducing hazard through the metalcatalysed Haber-Weiss reaction.

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Section: Discussionmentioning

confidence: 84%

Proapoptotic and redox state-related signaling of reactive oxygen species generated by transformed fibroblasts

Schimmel¹,

Bauer²

2002

Oncogene

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“…11 On the other hand, a number of reports support the opposing view that Src could inhibit apoptosis by downregulating proapoptotic genes 12 or upregulating anti-apoptotic genes. [13][14][15][16] In addition, Src is a potent activator of the PI3K/Akt pathway, which protects against pro-apoptotic stimuli via the phosphorylation and inactivation of death accelerators such as Bad, Bax and caspase-9. [17][18][19] Src-dependent activation of p38-MAPK similarly leads to the phosphorylation of caspases-8 and -3.…”

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confidence: 99%

Src tyrosine kinase inhibits apoptosis through the Erk1/2- dependent degradation of the death accelerator Bik

et al. 2012

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Src, the canonical member of the non-receptor family of tyrosine kinases, is deregulated in numerous cancers, including colon and breast cancers. In addition to its effects on cell proliferation and motility, Src is often considered as an inhibitor of apoptosis, although this remains controversial. Thus, whether the ability of Src to generate malignancies relies on an intrinsic aptitude to inhibit apoptosis or requires preexistent resistance to apoptosis remains somewhat elusive. Here, using mouse fibroblasts transformed with v-Src as a model, we show that the observed Src-dependent resistance to cell death relies on Src ability to inhibit the mitochondrial pathway of apoptosis by specifically increasing the degradation rate of the BH3-only protein Bik. This effect relies on the activation of the Ras-Raf-Mek1/2-Erk1/2 pathway, and on the phosphorylation of Bik on Thr124, driving Bik ubiquitylation on Lys33 and subsequent degradation by the proteasome. Importantly, in a set of human cancer cells with Src-, Kras-or BRAF-dependent activation of Erk1/2, resistances to staurosporine or thapsigargin were also shown to depend on Bik degradation rate via a similar mechanism. These results suggest that Bik could be a rate-limiting factor for apoptosis induction of tumor cells exhibiting deregulated Erk1/2 signaling, which may provide new opportunities for cancer therapies.

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“…Thus, STI571 may affect gene expression by reactivating pathways repressed by BCR/ABL. As v-SRC also represses the p38 MAK kinase (Johnson et al, 2000) and yet CCL9 levels are abundant in v-SRC-transformed 32Dcl3 cells, inhibition of the p38 MAP kinase, per se, might be insufficient to repress CCL9 expression and BCR/ABL-dependent regulation of other factors might be also required. The 3 0 untranslated region of …”

Section: Discussionmentioning

confidence: 99%

Expression of CCL9/MIP-1γ is repressed by BCR/ABL and its restoration suppresses in vivo leukemogenesis of 32D-BCR/ABL cells

et al. 2006

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Regulation of both apoptosis and cell survival by the v-Src oncoprotein

Abstract: A number of oncogenes alter the regulation of the cell cycle and cell death, contributing to the altered growth of tumours.

Cited by 69 publications

References 62 publications

Proapoptotic and redox state-related signaling of reactive oxygen species generated by transformed fibroblasts

Proapoptotic and redox state-related signaling of reactive oxygen species generated by transformed fibroblasts

Src tyrosine kinase inhibits apoptosis through the Erk1/2- dependent degradation of the death accelerator Bik

Expression of CCL9/MIP-1γ is repressed by BCR/ABL and its restoration suppresses in vivo leukemogenesis of 32D-BCR/ABL cells

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