Cyclin D1 promotes anchorage-independent cell survival by inhibiting FOXO-mediated anoikis
Open Access
- 3 July 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Differentiation
- Vol. 16 (10), 1408-1417
- https://doi.org/10.1038/cdd.2009.86
Abstract
O-class forkhead box (FOXO) transcription factors are critical regulators of diverse cellular processes, including apoptosis, cell-cycle arrest, DNA damage repair and oxidative stress resistance. Here, we show that FOXO1 and FOXO3a have an essential function in promoting cell detachment-induced anoikis, resistance to which is implicated in cancer development and metastasis. In contrast, the oncoprotein cyclin D1 inhibits anoikis. We further show that cyclin D1 interacts with FOXO proteins and impedes their transcriptional regulatory and anoikis-promoting functions. This effect of cyclin D1 requires its transcription repression domain but is independent of cyclin-dependent kinases CDK4 and CDK6. Moreover, we show that cancer-derived mutants of cyclin D1 are much more stable than wild-type cyclin D1 under anchorage-independent conditions and possess a greater antagonistic effect on FOXO-regulated anoikis and anchorage-independent growth of cancer cells. These data suggest that cyclin D1 may have a critical function in tumorigenesis and cancer metastasis by inhibiting the anoikis-promoting function of FOXO proteins.Keywords
This publication has 39 references indexed in Scilit:
- Localization determines function: N-terminally truncated NS5A fragments accumulate in the nucleus and impair HCV replicationJournal of Hepatology, 2009
- A Transcription-Independent Function of FOXO1 in Inhibition of Androgen-Independent Activation of the Androgen Receptor in Prostate Cancer CellsCancer Research, 2008
- Specific lentiviral shRNA-mediated knockdown of cyclin D1 in mantle cell lymphoma has minimal effects on cell survival and reveals a regulatory circuit with cyclin D2Leukemia, 2008
- CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription factorOncogene, 2008
- Multiple Oncogenic Pathway Signatures Show Coordinate Expression Patterns in Human Prostate TumorsPLOS ONE, 2008
- FOXO Proteins Regulate Tumor Necrosis Factor-related Apoptosis Inducing Ligand ExpressionPublished by Elsevier BV ,2002
- Addiction to Oncogenes--the Achilles Heal of CancerScience, 2002
- Protection against Anoikis and Down-regulation of Cadherin Expression by a Regulatable β-Catenin ProteinPublished by Elsevier BV ,2002
- Specific protection against breast cancers by cyclin D1 ablationNature, 2001
- Overexpression of cyclin D1 is associated with metastatic prostate cancer to bone.2000