Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity

Yang, Huiling; Zhao, Ruiying; Yang, Heng; Lee, Mong Hong

doi:10.1038/sj.onc.1208352

Cited by 75 publications

(59 citation statements)

References 46 publications

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“…Cell proliferation and tumorigenicity in nude mice induced by IKKb expression can be overridden by FOXO3 (Hu et al, 2004). Similarly, the expression of a constitutively active form of Foxo4 suppresses oncogene HER2-mediated tumorigenesis in nude mice (Yang et al, 2005). Taken together, these observations suggest that FOXOs are mediators of tumor suppression.…”

Section: Foxo In Cancermentioning

confidence: 52%

FOXOs, cancer and regulation of apoptosis

2008

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Forkhead box O (FOXO) transcription factors are involved in multiple signaling pathways and play critical roles in a number of physiological and pathological processes including cancer. The importance of FOXO factors ascribes them under multiple levels of regulation including phosphorylation, acetylation/deacetylation, ubiquitination and protein-protein interactions. As FOXO factors play a pivotal role in cell fate decision, mounting evidence suggests that FOXO factors function as tumor suppressors in a variety of cancers. FOXOs are actively involved in promoting apoptosis in a mitochondriaindependent and -dependent manner by inducing the expression of death receptor ligands, including Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand, and Bcl-2 family members, such as Bim, bNIP3 and Bcl-X L , respectively. An understanding of FOXO proteins and their biology will provide new opportunities for developing more effective therapeutic approaches to treat cancer.

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Section: Foxo In Cancermentioning

confidence: 52%

FOXOs, cancer and regulation of apoptosis

2008

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“…In resistant breast cancer cells, reintroduction of active FoxO3a can partially restore cell proliferative arrest and sensitivity to gefitinib. In line with this observation, it has also been shown that the introduction of an active form of FoxO4 sensitizes HER2-overexpressing cells to apoptosis induced by the chemotherapeutic agent 2-methoxyestradiol, and it is believed that the restoration of FoxO4-induced p27 Kip1 is at least in part responsible for such observation (Yang et al, 2005).…”

Section: Foxo-cell Cycle and Apoptosismentioning

confidence: 75%

Many forks in the path: cycling with FoxO

2008

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FoxO transcription factors are an evolutionary conserved subfamily of the forkhead transcription factors, characterized by the forkhead DNA-binding domain. FoxO factors regulate a number of cellular processes involved in cell-fate decisions in a cell-type-and environment-specific manner, including metabolism, differentiation, apoptosis and proliferation. A key mechanism by which FoxO determines cell fate is through regulation of the cell cycle machinery, and as such the cellular consequence of FoxO deregulation is often manifested through perturbation of the cell cycle. Consequently, the deregulation of FoxO factors is implicated in the development of numerous proliferative diseases, in particular cancer.

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“…Importantly, reconstitution of FOXO1a nuclear localization restores its transcriptional activity in PTENnull cells, leading to cell-cycle arrest and apoptosis (17). Also, forced expression of nuclear FOXO proteins has been shown to induce apoptosis in a wide range of cancer cells, including breast cancer and malignant melanoma, although it could also exert paradoxical oncogenic effects in specific tumor histotypes and genetic context (18)(19)(20)(21)(22)(23)(24).…”

Section: Oncogenic Signaling Pathways and Dysregulated Nucleocytoplasmentioning

confidence: 99%

Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

Conforti

Wang

Rodriguez

et al. 2015

Clinical Cancer Research

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A dynamic distribution between nucleus and cytoplasm (nucleocytoplasmic shuttling) is one of the control mechanisms adapted by normal cells to regulate the activity of a variety of molecules. Growing evidence suggests that dysregulation of the nucleocytoplasmic shuttling is involved in promoting abnormal cell survival, tumor progression, and drug resistance, and is associated with poor cancer prognosis. Aberrant nucleocytoplasmic shuttling in cancer cells may result from a hyperactive status of diverse signal-transduction pathways, such as the PI3K-AKT and MAPK pathways, or from alterations in the general nuclear import/export machinery. Among the large number of molecules involved in the shuttling process, exportin XPO1, also known as chromosome region maintenance 1, appears to play a particularly prominent role in pathogenesis of both hematological malignancies and solid tumors. Given the importance of nucleocytoplasmic shuttling in cancer pathogenesis and the rapidly expanding knowledge in this field, attempts have been made to develop compounds able to revert the aberrant nucleocytoplasmic shuttling. A promising new drug, , which belongs to the class of XPO1 inhibitors called selective inhibitors of nuclear export, is now being tested in phase I/II clinical trials.

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Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity

Cited by 75 publications

References 46 publications

FOXOs, cancer and regulation of apoptosis

FOXOs, cancer and regulation of apoptosis

Many forks in the path: cycling with FoxO

Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

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