Mechanism of Hypoxia-Induced NF-kappa B

TY - JOUR

T1 - Mechanism of Hypoxia-Induced NF-kappa B

A1 - Culver,Carolyn

A1 - Sundqvist,Anders

A1 - Mudie,Sharon

A1 - Melvin,Andrew

A1 - Xirodimas,Dimitris

A1 - Rocha,Sonia

AU - Culver,Carolyn

AU - Sundqvist,Anders

AU - Mudie,Sharon

AU - Melvin,Andrew

AU - Xirodimas,Dimitris

AU - Rocha,Sonia

PY - 2010/10/10

Y1 - 2010/10/10

N2 - <p>NF-kappa B activation is a critical component in the transcriptional response to hypoxia. However, the underlying mechanisms that control its activity under these conditions are unknown. Here we report that under hypoxic conditions, I kappa B kinase (IKK) activity is induced through a calcium/calmodulin-dependent kinase 2 (CaMK2)dependent pathway distinct from that for other common inducers of NF-kappa B. This process still requires IKK and the IKK kinase TAK1, like that for inflammatory inducers of NF-kappa B, but the TAK1-associated proteins TAB1 and TAB2 are not essential. IKK complex activation following hypoxia requires Ubc13 but not the recently identified LUBAC (linear ubiquitin chain assembly complex) ubiquitin conjugation system. In contrast to the action of other NF-kappa B inducers, IKK-mediated phosphorylation of I kappa B alpha does not result in its degradation. We show that this results from I kappa B alpha sumoylation by Sumo-2/3 on critical lysine residues, normally required for K-48-linked polyubiquitination. Furthermore, inhibition of specific Sumo proteases is sufficient to release RelA from I kappa B alpha and activate NF-kappa B target genes. These results define a novel pathway regulating NF-kappa Bactivation, important to its physiological role in human health and disease.</p>

AB - <p>NF-kappa B activation is a critical component in the transcriptional response to hypoxia. However, the underlying mechanisms that control its activity under these conditions are unknown. Here we report that under hypoxic conditions, I kappa B kinase (IKK) activity is induced through a calcium/calmodulin-dependent kinase 2 (CaMK2)dependent pathway distinct from that for other common inducers of NF-kappa B. This process still requires IKK and the IKK kinase TAK1, like that for inflammatory inducers of NF-kappa B, but the TAK1-associated proteins TAB1 and TAB2 are not essential. IKK complex activation following hypoxia requires Ubc13 but not the recently identified LUBAC (linear ubiquitin chain assembly complex) ubiquitin conjugation system. In contrast to the action of other NF-kappa B inducers, IKK-mediated phosphorylation of I kappa B alpha does not result in its degradation. We show that this results from I kappa B alpha sumoylation by Sumo-2/3 on critical lysine residues, normally required for K-48-linked polyubiquitination. Furthermore, inhibition of specific Sumo proteases is sufficient to release RelA from I kappa B alpha and activate NF-kappa B target genes. These results define a novel pathway regulating NF-kappa Bactivation, important to its physiological role in human health and disease.</p>

KW - ALTITUDE PULMONARY-EDEMA

KW - ARF TUMOR-SUPPRESSOR

KW - ENDOTHELIAL-CELLS

KW - TRANSCRIPTION FACTORS

KW - KINASE TAK1

KW - ACTIVATION

KW - PATHWAY

KW - OXYGEN

KW - ROLES

KW - TAB1

U2 - 10.1128/MCB.00409-10

DO - 10.1128/MCB.00409-10

M1 - Article

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 20

VL - 30

SP - 4901

EP - 4921

ER -