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Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors.


ABSTRACT: NF-kappaB (RelA) is constitutively active in many cancers, where it upregulates antiapoptotic and other oncogenic genes. While proinflammatory stimulus-induced NF-kappaB activation involves IKK-dependent nuclear translocation, mechanisms for maintaining constitutive NF-kappaB activity in tumors have not been elucidated. We show here that maintenance of NF-kappaB activity in tumors requires Stat3, which is also frequently constitutively activated in cancer. Stat3 prolongs NF-kappaB nuclear retention through acetyltransferase p300-mediated RelA acetylation, thereby interfering with NF-kappaB nuclear export. Stat3-mediated maintenance of NF-kappaB activity occurs in both cancer cells and tumor-associated hematopoietic cells. Both murine and human cancers display highly acetylated RelA, which is associated with Stat3 activity. This Stat3/NF-kappaB interaction is thus central to both the transformed and nontransformed elements in tumors.

SUBMITTER: Lee H 

PROVIDER: S-EPMC2777654 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors.

Lee Heehyoung H   Herrmann Andreas A   Deng Jie-Hui JH   Kujawski Maciej M   Niu Guilian G   Li Zhiwei Z   Forman Steve S   Jove Richard R   Pardoll Drew M DM   Yu Hua H  

Cancer cell 20090401 4


NF-kappaB (RelA) is constitutively active in many cancers, where it upregulates antiapoptotic and other oncogenic genes. While proinflammatory stimulus-induced NF-kappaB activation involves IKK-dependent nuclear translocation, mechanisms for maintaining constitutive NF-kappaB activity in tumors have not been elucidated. We show here that maintenance of NF-kappaB activity in tumors requires Stat3, which is also frequently constitutively activated in cancer. Stat3 prolongs NF-kappaB nuclear retent  ...[more]

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