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Deadly liaisons: fatal attraction between CCN matricellular proteins and the tumor necrosis factor family of cytokines.

Chen CC, Lau LF - J Cell Commun Signal (2009)

Bottom Line: Mechanistically, CCNs function through integrin alpha(6)beta(1) and the heparan sulfate proteoglycan (HSPG) syndecan-4 to induce reactive oxygen species (ROS) accumulation, which is essential for apoptotic synergism.Mutant CCN1 proteins defective for binding alpha(6)beta(1)-HSPGs are unable to induce ROS or apoptotic synergism with TNF cytokines.Further, knockin mice that express an alpha(6)beta(1)-HSPG-binding defective CCN1 are blunted in TNFalpha- and Fas-mediated apoptosis, indicating that CCN1 is a physiologic regulator of these processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607 USA.

ABSTRACT
Recent studies have revealed an unexpected synergism between two seemingly unrelated protein families: CCN matricellular proteins and the tumor necrosis factor (TNF) family of cytokines. CCN proteins are dynamically expressed at sites of injury repair and inflammation, where TNF cytokines are also expressed. Although TNFalpha is an apoptotic inducer in some cancer cells, it activates NFkappaB to promote survival and proliferation in normal cells, and its cytotoxicity requires inhibition of de novo protein synthesis or NFkappaB signaling. The presence of CCN1, CCN2, or CCN3 overrides this requirement and unmasks the apoptotic potential of TNFalpha, thus converting TNFalpha from a proliferation-promoting protein into an apoptotic inducer. These CCN proteins also enhance the cytotoxicity of other TNF cytokines, including LTalpha, FasL, and TRAIL. Mechanistically, CCNs function through integrin alpha(6)beta(1) and the heparan sulfate proteoglycan (HSPG) syndecan-4 to induce reactive oxygen species (ROS) accumulation, which is essential for apoptotic synergism. Mutant CCN1 proteins defective for binding alpha(6)beta(1)-HSPGs are unable to induce ROS or apoptotic synergism with TNF cytokines. Further, knockin mice that express an alpha(6)beta(1)-HSPG-binding defective CCN1 are blunted in TNFalpha- and Fas-mediated apoptosis, indicating that CCN1 is a physiologic regulator of these processes. These findings implicate CCN proteins as contextual regulators of the inflammatory response by dictating or enhancing the cytotoxicity of TNFalpha and related cytokines.

No MeSH data available.


Related in: MedlinePlus

Signaling crosstalk between CCN1 and TNFα or FasL. In fibroblasts, CCN1 acts through binding integrins α6β1, αvβ5, and the cell surface HSPG syndecan-4, leading to generation of ROS by several mechanisms that include the activities of 5-LOX, nSMases, and the mitochondria. A high level of ROS enhances and maintains the activation of the cellular kinases JNK, which targets c-FLIP for degradation and allows TNFα to activate caspases-8 and -10 and induce apoptosis, and p38 MAPK, which promotes FasL-induced Bax activation and cytochrome c release
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Fig4: Signaling crosstalk between CCN1 and TNFα or FasL. In fibroblasts, CCN1 acts through binding integrins α6β1, αvβ5, and the cell surface HSPG syndecan-4, leading to generation of ROS by several mechanisms that include the activities of 5-LOX, nSMases, and the mitochondria. A high level of ROS enhances and maintains the activation of the cellular kinases JNK, which targets c-FLIP for degradation and allows TNFα to activate caspases-8 and -10 and induce apoptosis, and p38 MAPK, which promotes FasL-induced Bax activation and cytochrome c release

Mentions: Although inhibition of de novo protein synthesis or NFκB signaling is the most common way to enable TNFα induction of apoptosis in normal cells, CCNs do not perturb either process. In addition, CCN1 and TNFα induces ~2-fold more apoptosis and with a much faster kinetics (4–6 h vs. 24 h) compared to apoptosis induction by cycloheximide and TNFα, further suggesting that CCN1 works through a distinct mechanism (Chen et al. 2007). Indeed, CCNs act through inducing the accumulation of a high level of ROS to override the anti-apoptotic effects of NFκB, thus unmasking the cytotoxicity of TNFα (Fig. 4). Both CCN1 and CCN2 induce ROS production in fibroblasts, and neutralization of ROS with chemical scavengers or inhibiting cellular mechanism of ROS production annihilates their apoptotic synergism with TNFα and FasL (Chen et al. 2007; Juric et al. 2009). TNFα alone induces a transient JNK activation and a low level of ROS that is quickly dampened by NFκB-induced anti-oxidant proteins. Despite NFκB actions, the combination of CCN1 and TNFα induces a sufficient amount of ROS to trigger a robust and biphasic activation of JNK (Chen et al. 2007). Upon CCN1/TNFα treatment, JNK activation occurs within 15 min. but transiently declines between 1 and 3 h after stimulation, most likely due to NFκB-induced synthesis of new phosphatases. Eventually CCN1-induced ROS may inhibit the newly synthesized phosphatases and a second phase of JNK activation occurs between 4 and 6 h after stimulation, concomitant with cell death. This second phase of JNK activation, which is not seen in TNFα stimulation alone, is essential for CCN1/TNFα-induced apoptosis.Fig. 4


Deadly liaisons: fatal attraction between CCN matricellular proteins and the tumor necrosis factor family of cytokines.

Chen CC, Lau LF - J Cell Commun Signal (2009)

Signaling crosstalk between CCN1 and TNFα or FasL. In fibroblasts, CCN1 acts through binding integrins α6β1, αvβ5, and the cell surface HSPG syndecan-4, leading to generation of ROS by several mechanisms that include the activities of 5-LOX, nSMases, and the mitochondria. A high level of ROS enhances and maintains the activation of the cellular kinases JNK, which targets c-FLIP for degradation and allows TNFα to activate caspases-8 and -10 and induce apoptosis, and p38 MAPK, which promotes FasL-induced Bax activation and cytochrome c release
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2821476&req=5

Fig4: Signaling crosstalk between CCN1 and TNFα or FasL. In fibroblasts, CCN1 acts through binding integrins α6β1, αvβ5, and the cell surface HSPG syndecan-4, leading to generation of ROS by several mechanisms that include the activities of 5-LOX, nSMases, and the mitochondria. A high level of ROS enhances and maintains the activation of the cellular kinases JNK, which targets c-FLIP for degradation and allows TNFα to activate caspases-8 and -10 and induce apoptosis, and p38 MAPK, which promotes FasL-induced Bax activation and cytochrome c release
Mentions: Although inhibition of de novo protein synthesis or NFκB signaling is the most common way to enable TNFα induction of apoptosis in normal cells, CCNs do not perturb either process. In addition, CCN1 and TNFα induces ~2-fold more apoptosis and with a much faster kinetics (4–6 h vs. 24 h) compared to apoptosis induction by cycloheximide and TNFα, further suggesting that CCN1 works through a distinct mechanism (Chen et al. 2007). Indeed, CCNs act through inducing the accumulation of a high level of ROS to override the anti-apoptotic effects of NFκB, thus unmasking the cytotoxicity of TNFα (Fig. 4). Both CCN1 and CCN2 induce ROS production in fibroblasts, and neutralization of ROS with chemical scavengers or inhibiting cellular mechanism of ROS production annihilates their apoptotic synergism with TNFα and FasL (Chen et al. 2007; Juric et al. 2009). TNFα alone induces a transient JNK activation and a low level of ROS that is quickly dampened by NFκB-induced anti-oxidant proteins. Despite NFκB actions, the combination of CCN1 and TNFα induces a sufficient amount of ROS to trigger a robust and biphasic activation of JNK (Chen et al. 2007). Upon CCN1/TNFα treatment, JNK activation occurs within 15 min. but transiently declines between 1 and 3 h after stimulation, most likely due to NFκB-induced synthesis of new phosphatases. Eventually CCN1-induced ROS may inhibit the newly synthesized phosphatases and a second phase of JNK activation occurs between 4 and 6 h after stimulation, concomitant with cell death. This second phase of JNK activation, which is not seen in TNFα stimulation alone, is essential for CCN1/TNFα-induced apoptosis.Fig. 4

Bottom Line: Mechanistically, CCNs function through integrin alpha(6)beta(1) and the heparan sulfate proteoglycan (HSPG) syndecan-4 to induce reactive oxygen species (ROS) accumulation, which is essential for apoptotic synergism.Mutant CCN1 proteins defective for binding alpha(6)beta(1)-HSPGs are unable to induce ROS or apoptotic synergism with TNF cytokines.Further, knockin mice that express an alpha(6)beta(1)-HSPG-binding defective CCN1 are blunted in TNFalpha- and Fas-mediated apoptosis, indicating that CCN1 is a physiologic regulator of these processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607 USA.

ABSTRACT
Recent studies have revealed an unexpected synergism between two seemingly unrelated protein families: CCN matricellular proteins and the tumor necrosis factor (TNF) family of cytokines. CCN proteins are dynamically expressed at sites of injury repair and inflammation, where TNF cytokines are also expressed. Although TNFalpha is an apoptotic inducer in some cancer cells, it activates NFkappaB to promote survival and proliferation in normal cells, and its cytotoxicity requires inhibition of de novo protein synthesis or NFkappaB signaling. The presence of CCN1, CCN2, or CCN3 overrides this requirement and unmasks the apoptotic potential of TNFalpha, thus converting TNFalpha from a proliferation-promoting protein into an apoptotic inducer. These CCN proteins also enhance the cytotoxicity of other TNF cytokines, including LTalpha, FasL, and TRAIL. Mechanistically, CCNs function through integrin alpha(6)beta(1) and the heparan sulfate proteoglycan (HSPG) syndecan-4 to induce reactive oxygen species (ROS) accumulation, which is essential for apoptotic synergism. Mutant CCN1 proteins defective for binding alpha(6)beta(1)-HSPGs are unable to induce ROS or apoptotic synergism with TNF cytokines. Further, knockin mice that express an alpha(6)beta(1)-HSPG-binding defective CCN1 are blunted in TNFalpha- and Fas-mediated apoptosis, indicating that CCN1 is a physiologic regulator of these processes. These findings implicate CCN proteins as contextual regulators of the inflammatory response by dictating or enhancing the cytotoxicity of TNFalpha and related cytokines.

No MeSH data available.


Related in: MedlinePlus