Kinome-wide functional genomics screen reveals a novel mechanism of TNFα-induced nuclear accumulation of the HIF-1α transcription factor in cancer cells.

Hypoxia-inducible factor-1 (HIF-1) and its most important subunit, HIF-1α, plays a central role in tumor progression by regulating genes involved in cancer cell survival, proliferation and metastasis. HIF-1α activity is associated with nuclear accumulation of the transcription factor and regulated b...

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Autores principales:	Angela Schoolmeesters, Daniel D Brown, Yuriy Fedorov
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5f578786337e439d93b93d3837a75d79
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spelling	oai:doaj.org-article:5f578786337e439d93b93d3837a75d792021-11-18T07:28:12ZKinome-wide functional genomics screen reveals a novel mechanism of TNFα-induced nuclear accumulation of the HIF-1α transcription factor in cancer cells.1932-620310.1371/journal.pone.0031270https://doaj.org/article/5f578786337e439d93b93d3837a75d792012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22355351/?tool=EBIhttps://doaj.org/toc/1932-6203Hypoxia-inducible factor-1 (HIF-1) and its most important subunit, HIF-1α, plays a central role in tumor progression by regulating genes involved in cancer cell survival, proliferation and metastasis. HIF-1α activity is associated with nuclear accumulation of the transcription factor and regulated by several mechanisms including modulation of protein stability and degradation. Among recent advances are the discoveries that inflammation-induced cytokines and growth factors affect protein accumulation of HIF-1α under normoxia conditions. TNFα, a major pro-inflammatory cytokine that promotes tumorigenesis is known as a stimulator of HIF-1α activity. To improve our understanding of TNFα-mediated regulation of HIF-1α nuclear accumulation we screened a kinase-specific siRNA library using a cell imaging-based HIF-1α-eGFP chimera reporter assay. Interestingly, this systematic analysis determined that depletion of kinases involved in conventional TNFα signaling (IKK/NFκB and JNK pathways) has no detrimental effect on HIF-1α accumulation. On the other hand, depletion of PRKAR2B, ADCK2, TRPM7, and TRIB2 significantly decreases the effect of TNFα on HIF-1α stability in osteosarcoma and prostate cancer cell lines. These newly discovered regulators conveyed their activity through a non-conventional RELB-depended NFκB signaling pathway and regulation of superoxide activity. Taken together our data allow us to conclude that TNFα uses a distinct and complex signaling mechanism to induce accumulation of HIF-1α in cancer cells. In summary, our results illuminate a novel mechanism through which cancer initiation and progression may be promoted by inflammatory cytokines, highlighting new potential avenues for fighting this disease.Angela SchoolmeestersDaniel D BrownYuriy FedorovPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 2, p e31270 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Angela Schoolmeesters Daniel D Brown Yuriy Fedorov Kinome-wide functional genomics screen reveals a novel mechanism of TNFα-induced nuclear accumulation of the HIF-1α transcription factor in cancer cells.
description	Hypoxia-inducible factor-1 (HIF-1) and its most important subunit, HIF-1α, plays a central role in tumor progression by regulating genes involved in cancer cell survival, proliferation and metastasis. HIF-1α activity is associated with nuclear accumulation of the transcription factor and regulated by several mechanisms including modulation of protein stability and degradation. Among recent advances are the discoveries that inflammation-induced cytokines and growth factors affect protein accumulation of HIF-1α under normoxia conditions. TNFα, a major pro-inflammatory cytokine that promotes tumorigenesis is known as a stimulator of HIF-1α activity. To improve our understanding of TNFα-mediated regulation of HIF-1α nuclear accumulation we screened a kinase-specific siRNA library using a cell imaging-based HIF-1α-eGFP chimera reporter assay. Interestingly, this systematic analysis determined that depletion of kinases involved in conventional TNFα signaling (IKK/NFκB and JNK pathways) has no detrimental effect on HIF-1α accumulation. On the other hand, depletion of PRKAR2B, ADCK2, TRPM7, and TRIB2 significantly decreases the effect of TNFα on HIF-1α stability in osteosarcoma and prostate cancer cell lines. These newly discovered regulators conveyed their activity through a non-conventional RELB-depended NFκB signaling pathway and regulation of superoxide activity. Taken together our data allow us to conclude that TNFα uses a distinct and complex signaling mechanism to induce accumulation of HIF-1α in cancer cells. In summary, our results illuminate a novel mechanism through which cancer initiation and progression may be promoted by inflammatory cytokines, highlighting new potential avenues for fighting this disease.
format	article
author	Angela Schoolmeesters Daniel D Brown Yuriy Fedorov
author_facet	Angela Schoolmeesters Daniel D Brown Yuriy Fedorov
author_sort	Angela Schoolmeesters
title	Kinome-wide functional genomics screen reveals a novel mechanism of TNFα-induced nuclear accumulation of the HIF-1α transcription factor in cancer cells.
title_short	Kinome-wide functional genomics screen reveals a novel mechanism of TNFα-induced nuclear accumulation of the HIF-1α transcription factor in cancer cells.
title_full	Kinome-wide functional genomics screen reveals a novel mechanism of TNFα-induced nuclear accumulation of the HIF-1α transcription factor in cancer cells.
title_fullStr	Kinome-wide functional genomics screen reveals a novel mechanism of TNFα-induced nuclear accumulation of the HIF-1α transcription factor in cancer cells.
title_full_unstemmed	Kinome-wide functional genomics screen reveals a novel mechanism of TNFα-induced nuclear accumulation of the HIF-1α transcription factor in cancer cells.
title_sort	kinome-wide functional genomics screen reveals a novel mechanism of tnfα-induced nuclear accumulation of the hif-1α transcription factor in cancer cells.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/5f578786337e439d93b93d3837a75d79
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Kinome-wide functional genomics screen reveals a novel mechanism of TNFα-induced nuclear accumulation of the HIF-1α transcription factor in cancer cells.

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