TRAF2 plays a dual role in NF‐κB‐dependent gene activation by mediating the TNF‐induced activation of p38 MAPK and IκB kinase pathways

Carpentier, Isabelle; Declercq, Wim; Malinin, Nikolay L.; Wallach, David; Fiers, Walter; Beyaert, Rudi

doi:10.1016/s0014-5793(98)00226-9

Cited by 60 publications

(47 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, in contrast to published reports in 293 cells (36,40), TRAF2 apparently does not mediate p38 MAPK activation in endothelial cells, because the phosphorylation of p38 MAPK was not affected by a dominant negative TRAF2. Thus, inhibition of ephrin A1 induction by dominant negative TRAF2 is mediated by the JNK pathway.…”

Section: P38 Mapk/jnk-dependent Induction Of Ephrin A1 By Tnf-␣contrasting

confidence: 99%

Tumor Necrosis Factor-α Induction of Endothelial Ephrin A1 Expression Is Mediated by a p38 MAPK- and SAPK/JNK-dependent but Nuclear Factor-κB-independent Mechanism

Cheng¹,

Chen

2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

Tumor necrosis factor-␣ (TNF-␣) is a multifunctional cytokine that induces a broad spectrum of responses including angiogenesis. Angiogenesis promoted by TNF-␣ is mediated, at least in part, by ephrin A1, a member of the ligand family for Eph receptor tyrosine kinases. Although TNF-␣ induces ephrin A1 expression in endothelial cells, the signaling pathways mediating ephrin A1 induction remain unknown. In this study, we investigated the signaling mechanisms of TNF-␣-dependent induction of ephrin A1 in endothelial cells. Both TNFR1 and TNFR2 appear to be involved in regulating ephrin A1 expression in endothelial cells, because neutralizing antibodies to either TNFR1 or TNFR2 inhibited TNF-␣-induced ephrin A1 expression. Inhibition of nuclear factor-B (NF-B) activation by a trans-dominant inhibitory isoform of mutant IB␣ did not affect ephrin A1 induction, suggesting that NF-B proteins are not major regulators of ephrin A1 expression. In contrast, ephrin A1 induction was blocked by inhibition of p38 mitogen-activated protein kinase (MAPK) or SAPK/ JNK, but not p42/44 MAPK, using either selective chemical inhibitors or dominant-negative forms of p38 MAPK or TNF receptor-associated factor 2. These findings indicate that TNF-␣-induced ephrin A1 expression is mediated through JNK and p38 MAPK signaling pathways. Taken together, the results of our study demonstrated that induction of ephrin A1 in endothelial cells by TNF-␣ is mediated through both p38 MAPK and SAPK/JNK, but not p42/44 MAPK or NF-B, pathways.Angiogenesis, the formation of new blood vessels, is a multistep process that includes endothelial cell proliferation, migration, capillary tube assembly, and recruitment of perivascular support cells to form mature and functional vessels (1, 2). This process is not only critical for embryogenesis and the normal function of the female reproductive tract but also plays an essential role under many pathological conditions such as wound healing, tumor growth and metastasis, and rheumatoid arthritis. Over the past decade, tremendous progress has been made in dissecting the molecular mechanisms underlying this important biological process. Receptor tyrosine kinases have emerged as critical molecules in regulating many aspects of angiogenesis (reviewed in Refs. 3 and 4). At least three families of receptor tyrosine kinases have been implicated in angiogenesis: the VEGF 1 family, the angiopoietin/Tie2 family, and the ephrin/Eph family. VEGFs are vascular endothelial cell growth factors that promote endothelial cell proliferation, migration, and vessel assembly. Members of the VEGF receptor family are crucial to de novo blood vessel formation during embryonic development and mediate angiogenesis in a number of diseases including inflammation and cancer. Members of the angiopoeitin/Tie2 family of receptor tyrosine kinases function in blood vessel remodeling, maturation, and stabilization. A third family, the Eph family, has recently been shown to significantly regulate angiogenesis.The Eph family comprises the largest subfami...

show abstract

Section: P38 Mapk/jnk-dependent Induction Of Ephrin A1 By Tnf-␣contrasting

confidence: 99%

Tumor Necrosis Factor-α Induction of Endothelial Ephrin A1 Expression Is Mediated by a p38 MAPK- and SAPK/JNK-dependent but Nuclear Factor-κB-independent Mechanism

Cheng¹,

Chen

2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The functional importance of p38 MAPK in MMP-2 expression in melanoma cells was also suggested by a recent report showing that inhibition of p38 MAPK by the specific inhibitor SB203580 down-regulated MMP-2 expression resulting in reduced invasive potential of malignant melanoma cells (45). Moreover, in different cell types, the p38 MAPK-dependent pathway interferes with the transactivation properties of NF-nB (46)(47)(48). Although the mechanisms by which p38 MAPK activates NF-nB are controversial, with evidence supporting regulation of NF-nBdependent gene transcription via modulation of activation of the transcription factor IID and/or post-translational modifications, including phosphorylation and acetylation, of the RelA/p65 subunit, our data strongly suggest that mda-9/syntenin stimulates MMP-2 expression by activating MT1-MMP through the p38 MAPK and NF-nB pathways leading to melanoma cell migration and invasion.…”

Section: Discussionmentioning

confidence: 99%

mda-9/Syntenin Regulates the Metastatic Phenotype in Human Melanoma Cells by Activating Nuclear Factor-κB

Boukerche¹,

Su²,

Emdad³

et al. 2007

Cancer Research

View full text Add to dashboard Cite

mda-9/Syntenin is a scaffolding PDZ domain-containing protein overexpressed in multiple human cancers that functions as a positive regulator of melanoma metastasis. Using a normal immortal human melanocyte cell line and weakly and highly metastatic human melanoma cell lines, we presently show that mda-9/syntenin initiates a signaling cascade that activates nuclear factor-KB (NF-KB) in human melanoma cells. As a consequence of elevated mda-9/syntenin expression, tumor cell growth and motility, fundamental components of tumor cell invasion and metastatic spread of melanoma cells, are enhanced through focal adhesion kinase (FAK)-induced and p38 mitogen-activated protein kinase (MAPK)-induced activation of NF-KB. Inhibiting mda-9/ syntenin, using an adenovirus expressing antisense mda-9/ syntenin, NF-KB, using an adenovirus expressing a mutant superrepressor of IKBA, or FAK, and using a dominantnegative mutant of FAK (FRNK), blocks melanoma cell migration, anchorage-independent growth, and invasion. Downstream signaling changes mediated by mda-9/syntenin, which include activation of FAK, p38 MAPK, and NF-KB, promote induction of membrane-type matrix metalloproteinase-1 that then activates pro-MMP-2-promoting migration and extracellular matrix invasion of melanoma cells. These results highlight the importance of mda-9/syntenin as a key component of melanoma metastasis providing a rational molecular target for potentially intervening in the metastatic process.

show abstract

“…They presented evidence that the p38 inhibitor SB203580 prevents NFkB nuclear translocation during ischemic adaptation. Similarly, tumor necrosis factor (TNF)-induced NFkB activity is blocked by p38 inhibitors (Beyaert et al, 1996;Carpentier et al, 1998). Carter et al (1999) presented that this regulation is in part dependent on the modulation of the activation of transcription factor IID (TFIID).…”

Section: Discussionmentioning

confidence: 99%

Loss of E-cadherin leads to upregulation of NFκB activity in malignant melanoma

Kuphal

Poser

Jobin³

et al. 2004

Oncogene

129

118

View full text Add to dashboard Cite

Malignant transformation of melanocytes frequently coincides with loss of E-cadherin expression. Here, we show that loss of E-cadherin leads to induction of nuclear factor kappa B (NFjB) activity in melanoma cell lines. Melanoma cells show constitutively active NFjB, whereas no activity is found in primary melanocytes. After reexpression of E-cadherin in melanoma cells, strong downregulation of NFjB activity was found. Consistently, NFjB activity was induced in primary human melanocytes after inhibition of E-cadherin activity by functionally blocking anti-E-cadherin antibodies. Interestingly, reexpression of E-cadherin-blocked p38 MAPK activity and the p38 MAPK inhibitors SB203580 and SB202190 almost completely prevented NFjB activation in melanoma cells. Furthermore, cytoplasmatic b-catenin induced p38 and NFjB activation in malignant melanoma. To our knowledge, this is the first report suggesting a correlation between E-cadherin and NFjB activity in melanocytes and melanoma cells. In summary, we conclude that loss of E-cadherin and cytoplasmatic b-catenin induces p38-mediated NFjB activation, potentially revealing an important mechanism of tumorigenesis in malignant melanomas.

show abstract

TRAF2 plays a dual role in NF‐κB‐dependent gene activation by mediating the TNF‐induced activation of p38 MAPK and IκB kinase pathways

Cited by 60 publications

References 22 publications

Tumor Necrosis Factor-α Induction of Endothelial Ephrin A1 Expression Is Mediated by a p38 MAPK- and SAPK/JNK-dependent but Nuclear Factor-κB-independent Mechanism

Tumor Necrosis Factor-α Induction of Endothelial Ephrin A1 Expression Is Mediated by a p38 MAPK- and SAPK/JNK-dependent but Nuclear Factor-κB-independent Mechanism

mda-9/Syntenin Regulates the Metastatic Phenotype in Human Melanoma Cells by Activating Nuclear Factor-κB

Loss of E-cadherin leads to upregulation of NFκB activity in malignant melanoma

Contact Info

Product

Resources

About