IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a

Mickey C.T. Hu; Dung Fang Lee; Weiya Xia; Leonard S. Golfman; Fu Ou-Yang; Jer Yen Yang; Yiyu Zou; Shilai Bao; Norihisa Hanada; Hitomi Saso; Ryuji Kobayashi; Mien Chie Hung

doi:10.1016/S0092-8674(04)00302-2

IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a

Mickey C.T. Hu, Dung Fang Lee, Weiya Xia, Leonard S. Golfman, Fu Ou-Yang, Jer Yen Yang, Yiyu Zou, Shilai Bao, Norihisa Hanada, Hitomi Saso, Ryuji Kobayashi, Mien Chie Hung

Research output: Contribution to journal › Article › peer-review

775 Scopus citations

Abstract

Nuclear exclusion of the forkhead transcription factor FOXO3a by protein kinase Akt contributes to cell survival. We investigated the pathological relationship between phosphoylated-Akt (Akt-p) and FOXO3a in primary tumors. Surprisingly, FOXO3a was found to be excluded from the nuclei of some tumors lacking Akt-p, suggesting an Akt-independent mechanism of regulating FOXO3a localization. We provide evidence for such a mechanism by showing that IκB kinase (IKK) physically interacts with, phosphorylates, and inhibits FOXO3a independent of Akt and causes proteolysis of FOXO3a via the Ub-dependent proteasome pathway. Cytoplasmic FOXO3a correlates with expression of IKKβ or Akt-p in many tumors and associates with poor survival in breast cancer. Further, constitutive expression of IKKβ promotes cell proliferation and tumorigenesis that can be overridden by FOXO3a. These results suggest the negative regulation of FOXO factors by IKK as a key mechanism for promoting cell growth and tumorigenesis.

Original language	English (US)
Pages (from-to)	225-237
Number of pages	13
Journal	Cell
Volume	117
Issue number	2
DOIs	https://doi.org/10.1016/S0092-8674(04)00302-2
State	Published - Apr 16 2004
Externally published	Yes

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/S0092-8674(04)00302-2

Cite this

@article{9feaf04ee065497b92854c29d44fdf52,

title = "IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a",

abstract = "Nuclear exclusion of the forkhead transcription factor FOXO3a by protein kinase Akt contributes to cell survival. We investigated the pathological relationship between phosphoylated-Akt (Akt-p) and FOXO3a in primary tumors. Surprisingly, FOXO3a was found to be excluded from the nuclei of some tumors lacking Akt-p, suggesting an Akt-independent mechanism of regulating FOXO3a localization. We provide evidence for such a mechanism by showing that IκB kinase (IKK) physically interacts with, phosphorylates, and inhibits FOXO3a independent of Akt and causes proteolysis of FOXO3a via the Ub-dependent proteasome pathway. Cytoplasmic FOXO3a correlates with expression of IKKβ or Akt-p in many tumors and associates with poor survival in breast cancer. Further, constitutive expression of IKKβ promotes cell proliferation and tumorigenesis that can be overridden by FOXO3a. These results suggest the negative regulation of FOXO factors by IKK as a key mechanism for promoting cell growth and tumorigenesis.",

author = "Hu, {Mickey C.T.} and Lee, {Dung Fang} and Weiya Xia and Golfman, {Leonard S.} and Fu Ou-Yang and Yang, {Jer Yen} and Yiyu Zou and Shilai Bao and Norihisa Hanada and Hitomi Saso and Ryuji Kobayashi and Hung, {Mien Chie}",

note = "Funding Information: We thank K. Arden, M. Greenberg, B. Burgering, C. Paya, K. Jeang, and P. Chiao for reagents; B. Spohn, L. Zhong, M. Lising, and A. Scott for technical supports; Z. Wang for statistical analysis; and L.-K. Su for funding support. This work was partially supported by grants from the Breast Cancer Research Program, start-up funds (M.H. and M.C.H.) from the M. D. Anderson Cancer Center, and grants from the Susan G. Komen Breast Cancer Foundation (BCTR0201848 M.H.), NIH RO1 (CA58880 M.C.H.), PO1 (CA99031 M.C.H.), and Cancer Center Supporting Grant CA16772.",

year = "2004",

month = apr,

day = "16",

doi = "10.1016/S0092-8674(04)00302-2",

language = "English (US)",

volume = "117",

pages = "225--237",

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TY - JOUR

T1 - IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a

AU - Hu, Mickey C.T.

AU - Lee, Dung Fang

AU - Xia, Weiya

AU - Golfman, Leonard S.

AU - Ou-Yang, Fu

AU - Yang, Jer Yen

AU - Zou, Yiyu

AU - Bao, Shilai

AU - Hanada, Norihisa

AU - Saso, Hitomi

AU - Kobayashi, Ryuji

AU - Hung, Mien Chie

N1 - Funding Information: We thank K. Arden, M. Greenberg, B. Burgering, C. Paya, K. Jeang, and P. Chiao for reagents; B. Spohn, L. Zhong, M. Lising, and A. Scott for technical supports; Z. Wang for statistical analysis; and L.-K. Su for funding support. This work was partially supported by grants from the Breast Cancer Research Program, start-up funds (M.H. and M.C.H.) from the M. D. Anderson Cancer Center, and grants from the Susan G. Komen Breast Cancer Foundation (BCTR0201848 M.H.), NIH RO1 (CA58880 M.C.H.), PO1 (CA99031 M.C.H.), and Cancer Center Supporting Grant CA16772.

PY - 2004/4/16

Y1 - 2004/4/16

N2 - Nuclear exclusion of the forkhead transcription factor FOXO3a by protein kinase Akt contributes to cell survival. We investigated the pathological relationship between phosphoylated-Akt (Akt-p) and FOXO3a in primary tumors. Surprisingly, FOXO3a was found to be excluded from the nuclei of some tumors lacking Akt-p, suggesting an Akt-independent mechanism of regulating FOXO3a localization. We provide evidence for such a mechanism by showing that IκB kinase (IKK) physically interacts with, phosphorylates, and inhibits FOXO3a independent of Akt and causes proteolysis of FOXO3a via the Ub-dependent proteasome pathway. Cytoplasmic FOXO3a correlates with expression of IKKβ or Akt-p in many tumors and associates with poor survival in breast cancer. Further, constitutive expression of IKKβ promotes cell proliferation and tumorigenesis that can be overridden by FOXO3a. These results suggest the negative regulation of FOXO factors by IKK as a key mechanism for promoting cell growth and tumorigenesis.

AB - Nuclear exclusion of the forkhead transcription factor FOXO3a by protein kinase Akt contributes to cell survival. We investigated the pathological relationship between phosphoylated-Akt (Akt-p) and FOXO3a in primary tumors. Surprisingly, FOXO3a was found to be excluded from the nuclei of some tumors lacking Akt-p, suggesting an Akt-independent mechanism of regulating FOXO3a localization. We provide evidence for such a mechanism by showing that IκB kinase (IKK) physically interacts with, phosphorylates, and inhibits FOXO3a independent of Akt and causes proteolysis of FOXO3a via the Ub-dependent proteasome pathway. Cytoplasmic FOXO3a correlates with expression of IKKβ or Akt-p in many tumors and associates with poor survival in breast cancer. Further, constitutive expression of IKKβ promotes cell proliferation and tumorigenesis that can be overridden by FOXO3a. These results suggest the negative regulation of FOXO factors by IKK as a key mechanism for promoting cell growth and tumorigenesis.

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JO - Cell

JF - Cell

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ER -

IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a

Abstract

ASJC Scopus subject areas

UN SDGs

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