IL-2 deprivation triggers apoptosis which is mediated by c-Jun N-terminal kinase 1 activation and prevented by Bcl-2

Cerezo, Ana B.; Martı́nez-A, Carlos; González, Ana; Gómez, Javier; Rebollo, Angelita

doi:10.1038/sj.cdd.4400458

Cited by 20 publications

(12 citation statements)

References 33 publications

(40 reference statements)

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“…Alternative splicing aects the apoptotic properties of ITM2B; ITM2B s acts as a proapoptotic protein whereas ITM2B L does not induce apoptosis in IL-2-stimulated cells. In addition, ITM2B s is not able to induce apoptosis in IL-4-stimulated cells, indicating that the observed apoptotic eect of ITM2B s in IL-2-stimulated or -deprived cells is physiologically relevant and that the mechanisms that control apoptosis via IL-2R and IL-4R are dierent, as it has been previously shown (Cerezo et al, 1998(Cerezo et al, , 1999Rebollo et al, 2000). The results presented here show a new role for ITM2B s as an apoptotic-associated gene with a BH3 domain that appears upon IL-2-deprivation, a stimulus that trigger apoptosis.…”

Section: Discussionmentioning

confidence: 59%

Proapoptotic activity of ITM2Bs, a BH3-only protein induced upon IL-2-deprivation which interacts with Bcl-2

et al. 2002

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Growth factor deprivation is a physiological mechanism to induce apoptosis. We used an IL-2-dependent murine T cell line to identify proteins that trigger apoptosis. Here we report the identi®cation, the cloning and characterization of ITM2B s , a protein induced upon IL-2-deprivation. ITM2B s , which shares the BH3 domain of Bcl-2 family members, is a cytoplasmic and mitochondrial protein. Expression of ITM2B s induces apoptosis in IL-2-stimulated cells, but not in IL-4-stimulated cells, while overexpression of the long form of the protein is not able to induce apoptosis. In IL-2-stimulated cells, ITM2B s interacts with the antiapoptotic protein Bcl-2, and does not interact with the proapoptotic Bad. Mutation of the critical L and D residues within the BH3 domain abolished the ability of ITM2B s to promote apoptosis.

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Section: Discussionmentioning

confidence: 59%

Proapoptotic activity of ITM2Bs, a BH3-only protein induced upon IL-2-deprivation which interacts with Bcl-2

et al. 2002

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“…In the case of the JNK cascade, differential involvement of SAPK/JNK isoforms in growth regulation and apoptosis induction has been demonstrated in several different cell types (38,39). To determine whether MLK2 activation of the SAPK pathway leads to preferential activation of JNK isoforms, COS7 cells were cotransfected with expression plasmids for HA-MLK2 ( Fig.…”

Section: Mlk2mentioning

confidence: 99%

Activated JNK Phosphorylates the C-terminal Domain of MLK2 That Is Required for MLK2-induced Apoptosis

Phelan

Price

Liu

et al. 2001

Journal of Biological Chemistry

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One mechanism by which cells respond to extracellular stimuli is the recruitment of signaling networks that regulate changes in the internal environment and control gene transcription (reviewed in Refs. 1 and 2). A group of signaling pathways that are highly conserved through evolution are collectively known as mitogen-activated protein kinase (MAPK) 1 pathways (3, 4). The classical MAPK pathway is triggered by growth factors binding to cell surface receptors leading to the activation of the GTPase, Ras. This pathway results in activation of the extracellular signal-regulated kinases (ERKs) leading to gene transcription and cellular proliferation. A parallel MAPK pathway triggered by stress factors such as osmotic shock, UV irradiation, cytotoxic drugs, and inflammatory cytokines results in activation of the stress-activated protein kinase/c-Jun N-terminal kinases (SAPK/JNKs) (2). A second stress-activated pathway leads to activation of p38 MAPK. Effects of stress activation vary from proliferation, differentiation, and gene transcription to cell cycle arrest and apoptosis depending on cell type and stimulus (2).All MAPK pathways utilize a "three-kinase cascade" mechanism to modulate incoming signals. Thus, each MAPK has upstream-activating kinases (MAPKKs) that are in turn regulated by MAPKK kinases (MAPKKKs) (reviewed in Ref. 5). Some of the upstream kinases appear to be highly specific for a particular cascade, whereas others link to more than one MAPK. The MAPKKs for the ERKs are the MAP/ERK kinases (MEKs) (6 -8), whereas activators for JNKs are the SAPK/ERK kinase/JNK kinase (SEK1/JNKK), also known as MAPK kinase 4 (MKK4) (9 -11), and the more recently discovered MKK7 (12)(13)(14). In the case of p38, the main upstream-activating kinases are MKK3 and MKK6 (11,15,16), but p38 can also be activated by JNKK/MKK4 (11), providing crossover between the JNK and the p38 pathways. MAPKKKs are a larger group of kinases that have overlapping specificities for MAPKKs and are themselves activated by an array of interactions in response to extracellular and internal stimuli (reviewed in Ref. 17). As more upstream activators of the MAPKs are identified, the picture of how these three parallel pathways are regulated becomes more complex.Recently it has become clear that MAPKs not only control downstream signals to transcription factors but also exert effects upstream on their activators. In budding yeast, the three components of the pheromone-induced MAPK cascade are Ste11 f Ste7 f Fus3/KSS (18). Errede and co-workers (19) coined the term "feedback phosphorylation" to describe upstream phosphorylation of Ste7 by Fus3. In mammalian cells, Xu and Cobb (20) report that JNK binds to and phosphorylates

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“…Some of these responses are unique to IL-4, whereas others are also elicited by different cytokines. Although the receptors for IL-2 and IL-4 have several features in common, including their use of the ␥ chain as a receptor component, IL-4 evokes responses that IL-2 does not (9,18,26,34). Many factor-dependent cell lines respond to IL-4 with increased thymidine incorporation into DNA, but only a few lines have been successfully adapted for growth in IL-4 alone.…”

mentioning

confidence: 99%

Bcl-3 Expression Promotes Cell Survival following Interleukin-4 Deprivation and Is Controlled by AP1 and AP1-Like Transcription Factors

Rebollo

Dumoutier

Renauld

et al. 2000

Molecular and Cellular Biology

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IL-2 deprivation triggers apoptosis which is mediated by c-Jun N-terminal kinase 1 activation and prevented by Bcl-2

Cited by 20 publications

References 33 publications

Proapoptotic activity of ITM2Bs, a BH3-only protein induced upon IL-2-deprivation which interacts with Bcl-2

Proapoptotic activity of ITM2Bs, a BH3-only protein induced upon IL-2-deprivation which interacts with Bcl-2

Activated JNK Phosphorylates the C-terminal Domain of MLK2 That Is Required for MLK2-induced Apoptosis

Bcl-3 Expression Promotes Cell Survival following Interleukin-4 Deprivation and Is Controlled by AP1 and AP1-Like Transcription Factors

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