Type

Journal Article

Authors

Cormac T. Taylor
Jacques Pouyssegur
Paul Moynagh
Jens E Nielsen
Catherine Godson
Fergal Seeballuck
Kathleen T. Fitzgerald
Amandine Ginouves
Katrina M Comerford
Edurne Berra
and 1 others

Subjects

Biochemistry

Topics
i kappa b kinase procollagen proline dioxygenase metabolism humans pharmacology drug effects cell nucleus chemistry amino acid sequence protein binding nf kappa b molecular sequence data genetics cell hypoxia cell line tumor necrosis factor alpha

Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. (2006)

Abstract Hypoxia is a feature of the microenvironment of a growing tumor. The transcription factor NFkappaB is activated in hypoxia, an event that has significant implications for tumor progression. Here, we demonstrate that hypoxia activates NFkappaB through a pathway involving activation of IkappaB kinase-beta (IKKbeta) leading to phosphorylation-dependent degradation of IkappaBalpha and liberation of NFkappaB. Furthermore, through increasing the pool and/or activation potential of IKKbeta, hypoxia amplifies cellular sensitivity to stimulation with TNFalpha. Within its activation loop, IKKbeta contains an evolutionarily conserved LxxLAP consensus motif for hydroxylation by prolyl hydroxylases (PHDs). Mimicking hypoxia by treatment of cells with siRNA against PHD-1 or PHD-2 or the pan-prolyl hydroxylase inhibitor DMOG results in NFkappaB activation. Conversely, overexpression of PHD-1 decreases cytokine-stimulated NFkappaB reporter activity, further suggesting a repressive role for PHD-1 in controlling the activity of NFkappaB. Hypoxia increases both the expression and activity of IKKbeta, and site-directed mutagenesis of the proline residue (P191A) of the putative IKKbeta hydroxylation site results in a loss of hypoxic inducibility. Thus, we hypothesize that hypoxia releases repression of NFkappaB activity through decreased PHD-dependent hydroxylation of IKKbeta, an event that may contribute to tumor development and progression through amplification of tumorigenic signaling pathways.
Collections Ireland -> University College Dublin -> PubMed

Full list of authors on original publication

Cormac T. Taylor, Jacques Pouyssegur, Paul Moynagh, Jens E Nielsen, Catherine Godson, Fergal Seeballuck, Kathleen T. Fitzgerald, Amandine Ginouves, Katrina M Comerford, Edurne Berra and 1 others

Experts in our system

1
Cormac T. Taylor
University College Dublin
Total Publications: 103
 
2
Paul N. Moynagh
Maynooth University
Total Publications: 81
 
3
Jens Erik Nielsen
University College Dublin
Total Publications: 27
 
4
Catherine Godson
University College Dublin
Total Publications: 90
 
5
Kathleen T. Fitzgerald
University College Dublin
Total Publications: 6