HTLV-I Tax Protein Binds to MEKK1 to Stimulate IκB Kinase Activity and NF-κB Activation

Yin, Min; Christerson, Lori B.; Yamamoto, Yumi; Kwak, Youn Tae; Xu, Shuichan; Mercurio, Frank; Barbosa, Miguel; Cobb, Melanie H.; Gaynor, Richard B.

doi:10.1016/s0092-8674(00)81447-6

Cited by 250 publications

(271 citation statements)

References 43 publications

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“…More recently, MEKK1 was also proposed to be involved in NF-B activation (F.S. Yin et al 1998). Although MEKK1 overexpression causes IKK activation (Lee et al 1998), this effect is weaker than the effect on JNK activity (Karin and Delhase 1998).…”

Section: Discussionmentioning

confidence: 99%

Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain

Baud¹,

Liu²,

Bennett³

et al. 1999

Genes & Development

426

359

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Section: Discussionmentioning

confidence: 99%

Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain

Baud¹,

Liu²,

Bennett³

et al. 1999

Genes & Development

426

359

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“…27,28 The Tax protein from the leukemogenic virus HTLV-1 is a potent activator of Rel/NF-B and the growth of Taxinduced tumors in mice is inhibited by antisense relA constructs. 29 Tax-mediated activation of NF-B resulted from direct interactions of Tax and MEKK1, a component of an I B kinase complex, and the interaction of Tax and MEKK1 enhances phosphorylation of I B by I B kinase. 30 Activation of NF-B by the HBV x gene has been reported in liver and nonliver cell lines.…”

Section: Discussionmentioning

confidence: 99%

Role of Rel/NF‐κB transcription factors in apoptosis of human hepatocellular carcinoma cells

Chiao¹,

Ren²,

Niu³

et al. 2002

Cancer

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BACKGROUNDPrimary hepatocellular carcinoma (HCC) is one of the 10 most common human carcinomas in the world. The mechanism by which HCC cells resist apoptosis induced by various treatment modalities is poorly understood.METHODSThe authors sought to determine whether Rel/NF‐κB transcription factors play a key role in controlling apoptosis in human HCCcells. We assessed constitutive and inducible activation of NF‐κB in hepatitis B virus (HBV)‐positive (Hep3B) and in hepatitis virus‐negative (Chang, HepG2) HCC cells, as well as the role of known inhibitors of NF‐κB activity.RESULTSThe current study data demonstrate that 1) RelA/NF‐κB activity is activated constitutively in Hep3B cells, as determined by electrophoretic mobility shift assays; 2) RelA/NF‐κB reporter gene activity is inhibited specifically by dominant‐negative mutants of IκBα, IKK1, IKK2, MEKK1, and MEKK3 and it is activated by overexpression of wild‐type MEKK3, suggesting that upstream kinase cascades induce phosphorylation of IκBα and activate RelA/NF‐κB in Hep3B cells; 3) overexpression of the HBV x gene fails to activate NF‐κB in HepG2 and Chang cell lines; 4) The NF‐κB–inducible gene, bcl‐xl, is overexpressed in Hep3B cells and is inhibited by the proteosome inhibitor PS341, which prevents IκBα degradation and RelA/NF‐κB activation; and 5) inhibition of constitutive RelA/NF‐κB activity by PS341 sensitizes Hep3B cells to doxorubicin‐induced apoptosis.CONCLUSIONSThese results are consistent with the role of RelA/NF‐κB activity in the regulation of apoptosis through activation of its downstream target genes and suggest that signaling pathways that control RelA/NF‐κB activity may be important targets for novel therapeutic approaches in the treatment of human HCC. Cancer 2002;95:1696–705. © 2002 American Cancer Society.DOI 10.1002/cncr.10829

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“…Interestingly, PKCδ has also been implicated in the activation of MEKK1, a Mek kinase involved in the activation of ERK1/2 and JNK [166,167]. Several studies have reported a role for MEKK1 in the regulation of NFκB activity through its ability to mediate IKK activation [99,171]. This raises the interesting possibility that PKCδ may mediate IL-1β-dependent increases in iNOS expression through its ability to drive ERK1/2 along with its ability to increase NF-κB activity in a more direct manner.…”

Section: It Is Not Surprising That Pkcδ Is Involved In This Cytokine-mentioning

confidence: 99%

Regulation of smooth muscle by inducible nitric oxide synthase and NADPH oxidase in vascular proliferative diseases

Ginnan

Guikema

Halligan

et al. 2008

Free Radical Biology and Medicine

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Inflammation plays a critical role in promoting smooth muscle migration and proliferation during vascular diseases such as post-angioplasty restenosis and atherosclerosis. Another common feature of many vascular diseases is the contribution of reactive oxygen (ROS) and nitrogen (RNS) species to vascular injury. Primary sources of ROS and RNS in smooth muscle are several isoforms of NADPH oxidase (Nox) and the cytokine-regulated inducible nitric oxide (NO) synthase (iNOS). One important example of the interaction between NO and ROS is the reaction of NO with superoxide to yield peroxynitrite, which may contribute to the pathogenesis of hypertension. In this review, we discuss the literature that supports an alternate possibility: Nox-derived ROS modulate NO bioavailability by altering the expression of iNOS. We highlight data showing co-expression of iNOS and Nox in vascular smooth muscle and demonstrating the functional consequences of iNOS and Nox during vascular injury. We describe the relevant literature demonstrating that the mitogen activated protein kinases (MAP kinases) are important modulators of pro-inflammatory cytokinedependent expression of iNOS. A central hypothesis discussed is that ROS-dependent regulation of the serine/threonine kinase protein kinase Cδ (PKCδ) is essential to understanding how Nox may regulate signaling pathways leading to iNOS expression. Overall, the integration of non-phagocytic NADPHoxidase with cytokine signaling in general and in vascular smooth muscle in particular is poorly understood and merit further investigation.

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HTLV-I Tax Protein Binds to MEKK1 to Stimulate IκB Kinase Activity and NF-κB Activation

Cited by 250 publications

References 43 publications

Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain

Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain

Role of Rel/NF‐κB transcription factors in apoptosis of human hepatocellular carcinoma cells

Regulation of smooth muscle by inducible nitric oxide synthase and NADPH oxidase in vascular proliferative diseases

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