Regulation of the cytoskeleton: an oncogenic function for cdk inhibitors?

Besson, Arnaud; Assoian, Richard K.; Roberts, James M.

doi:10.1038/nrc1501

Cited by 178 publications

(180 citation statements)

References 59 publications

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“…This raises the possibility that the role of p21 in tumorigenesis is influenced by its subcellular localization. Consequently, whereas nuclear p21 inhibits CDK activity and halts cell-cycle progression, cytoplasmic p21 has an opposite function, contributing to oncogenesis 90 . Cytoplasmic p21 can interact with, and thereby inactivate, multiple pro-apoptotic proteins such as SAPK (also known as JNK) 91 , pro-caspase 3 (REF.…”

Section: Is P21 Required For Oncogenic Transformation?mentioning

confidence: 99%

KLF4, p21 and context-dependent opposing forces in cancer

2005

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| Krüppel-like factors are transcriptional regulators that influence several cellular functions, including proliferation. Recent studies have shown that one family member, KLF4, can function both as a tumour suppressor and an oncogene. The ability of KLF4 to affect the levels of expression of the cell-cycle regulator p21 seems to be involved, in that this protein might function as a switch that determines the outcome of KLF4 signalling. Is this role of p21 restricted to KLF4, or does p21 represent a nodal point for signals from multiple other factors with opposing functions in cancer?

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Section: Is P21 Required For Oncogenic Transformation?mentioning

confidence: 99%

KLF4, p21 and context-dependent opposing forces in cancer

2005

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“…It is a cyclin-dependent kinase (Cdk) inhibitor (CKI) that inhibits a variety of cyclin/ Cdk complexes including cyclin D/Cdk4/6 and cyclin E/Cdk2. The p27 mediates arrest at G1 of the cell cycle in response to transforming growth factor β (TGF-β), contact inhibition, or serum deprivation in epithelial cell lines [12][13][14]. Mice deficient for p27 display increased body size and enlarged organs, which contain more cells than wild type [15][16][17].…”

Section: The Role Of Cell Proliferation In Size Controlmentioning

confidence: 99%

Molecular mechanism of size control in development and human diseases

Yang

2011

Cell Res

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How multicellular organisms control their size is a fundamental question that fascinated generations of biologists. In the past 10 years, tremendous progress has been made toward our understanding of the molecular mechanism underlying size control. Original studies from Drosophila showed that in addition to extrinsic nutritional and hormonal cues, intrinsic mechanisms also play important roles in the control of organ size during development. Several novel signaling pathways such as insulin and Hippo-LATS signaling pathways have been identified that control organ size by regulating cell size and/or cell number through modulation of cell growth, cell division, and cell death. Later studies using mammalian cell and mouse models also demonstrated that the signaling pathways identified in flies are also conserved in mammals. Significantly, recent studies showed that dysregulation of size control plays important roles in the development of many human diseases such as cancer, diabetes, and hypertrophy.

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“…Indeed, some studies have indicated that p27 levels in tumors do not always correlate with proliferative index, and increasing evidence points to the importance of the subcellular localization of p27 in the control of its function, with cytoplasmic localization being a negative prognostic factor in certain instances (Singh et al 1998;Nakasu et al 1999;Saez et al 1999;Sanchez-Beato et al 1999;Slingerland and Pagano 2000;Philipp-Staheli et al 2001;Kouvaraki et al 2002;Liang et al 2002;Besson et al 2004a;Rosen et al 2005;Qi et al 2006). This possibility is supported by in vivo studies: p27 +/− mice are more susceptible to tumor development than p27 −/− animals in mammary and prostate tumor models, suggesting an active contribution of the remaining p27 allele (Muraoka et al 2002;Gao et al 2004).…”

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confidence: 99%

Discovery of an oncogenic activity in p27^Kip1that causes stem cell expansion and a multiple tumor phenotype

Besson¹,

Hwang²,

Cicero³

et al. 2007

Genes Dev.

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The cell cycle inhibitor p27 Kip1 also has cyclin-cyclin-dependent kinase (CDK)-independent functions. To investigate the significance of these functions in vivo, we generated a knock-in mouse in which four amino acid substitutions in the cdkn1b gene product prevent its interaction with cyclins and CDKs (p27 CK − ). In striking contrast to complete deletion of the cdkn1b gene, which causes spontaneous tumorigenesis only in the pituitary, the p27 CK − protein dominantly caused hyperplastic lesions and tumors in multiple organs, including the lung, retina, pituitary, ovary, adrenals, spleen, and lymphomas. Moreover, the high incidence of spontaneous tumors in the lung and retina was associated with amplification of stem/progenitor cell populations. Therefore, independently of its role as a CDK inhibitor, p27 Kip1 promoted stem cell expansion and functioned as a dominant oncogene in vivo. Thus, the p27 CK − mouse unveils a dual role for p27 during tumorigenesis: It is a tumor suppressor by virtue of its cyclin-CDK regulatory function, and also an oncogene through a cyclin-CDK-independent function. This may explain why the cdkn1b gene is rarely inactivated in human tumors, and the p27 CK − mouse in which the tumor suppressor function is lost but the cyclin-CDK-independent-oncogenic-function is maintained may represent a more faithful model for the widespread role of p27 misregulation in human cancers than the p27 null.[Keywords: p27 Kip1 ; lung tumor; oncogene; retina; bronchioalveolar stem cell; desquamative interstitial pneumonitis] Supplemental material is available at http://www.genesdev.org.

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Regulation of the cytoskeleton: an oncogenic function for cdk inhibitors?

Cited by 178 publications

References 59 publications

KLF4, p21 and context-dependent opposing forces in cancer

KLF4, p21 and context-dependent opposing forces in cancer

Molecular mechanism of size control in development and human diseases

Discovery of an oncogenic activity in p27^Kip1that causes stem cell expansion and a multiple tumor phenotype

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Regulation of the cytoskeleton: an oncogenic function for cdk inhibitors?

Cited by 178 publications

References 59 publications

KLF4, p21 and context-dependent opposing forces in cancer

KLF4, p21 and context-dependent opposing forces in cancer

Molecular mechanism of size control in development and human diseases

Discovery of an oncogenic activity in p27Kip1that causes stem cell expansion and a multiple tumor phenotype

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Product

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Discovery of an oncogenic activity in p27^Kip1that causes stem cell expansion and a multiple tumor phenotype