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A NIK-IKK? module expands ErbB2-induced tumor-initiating cells by stimulating nuclear export of p27/Kip1.

ABSTRACT: I?B kinase ? (IKK?) activity is required for ErbB2-induced mammary tumorigenesis. Here, we show that IKK? and its activator, NF-?B-inducing kinase (NIK), support the expansion of tumor-initiating cells (TICs) that copurify with a CD24(med)CD49f(hi) population from premalignant ErbB2-expressing mammary glands. Upon activation, IKK? enters the nucleus, phosphorylates the cyclin-dependent kinase (CDK) inhibitor p27/Kip1, and stimulates its nuclear export or exclusion. Reduced p27 expression rescues mammary tumorigenesis in mice deficient in IKK? kinase activity and restores TIC self-renewal. IKK? is also likely to be involved in human breast cancer, where its expression shows an inverse correlation with metastasis-free survival, and its presence in the nucleus of invasive ductal carcinomas (IDCs) is associated with decreased nuclear p27 abundance.

SUBMITTER: Zhang W

PROVIDER: S-EPMC3981467 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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A NIK-IKKα module expands ErbB2-induced tumor-initiating cells by stimulating nuclear export of p27/Kip1.

Zhang Weizhou W Tan Wei W Wu Xuefeng X Poustovoitov Maxim M Strasner Amy A Li Wei W Borcherding Nicholas N Ghassemian Majid M Karin Michael M

Cancer cell 20130418 5

IκB kinase α (IKKα) activity is required for ErbB2-induced mammary tumorigenesis. Here, we show that IKKα and its activator, NF-κB-inducing kinase (NIK), support the expansion of tumor-initiating cells (TICs) that copurify with a CD24(med)CD49f(hi) population from premalignant ErbB2-expressing mammary glands. Upon activation, IKKα enters the nucleus, phosphorylates the cyclin-dependent kinase (CDK) inhibitor p27/Kip1, and stimulates its nuclear export or exclusion. Reduced p27 expression rescues ...[more]

PMID: 23602409

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IKK-?/NF-?B p65 mediates p27(Kip1) protein degradation in arsenite response.

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Discovery of Small Molecules that Inhibit the Disordered Protein, p27(Kip1).

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