Liu, Y. et al. Somatic cell type specific gene transfer reveals a tumor-promoting function for p21Waf1/Cip1. EMBO J. 26, 4683-4693

Department of Molecular Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
The EMBO Journal (Impact Factor: 10.43). 12/2007; 26(22):4683-93. DOI: 10.1038/sj.emboj.7601886
Source: PubMed


How proteins participate in tumorigenesis can be obscured by their multifunctional nature. For example, depending on the cellular context, the cdk inhibitors can affect cell proliferation, cell motility, apoptosis, receptor tyrosine kinase signaling, and transcription. Thus, to determine how a protein contributes to tumorigenesis, we need to evaluate which functions are required in the developing tumor. Here we demonstrate that the RCAS/TvA system, originally developed to introduce oncogenes into somatic cells of mice, can be adapted to allow us to define the contribution that different functional domains make to tumor development. Studying the development of growth-factor-induced oligodendroglioma, we identified a critical role for the Cy elements in p21, and we showed that cyclin D1T286A, which accumulates in the nucleus of p21-deficient cells and binds to cdk4, could bypass the requirement for p21 during tumor development. These genetic results suggest that p21 acts through the cyclin D1-cdk4 complex to support tumor growth, and establish the utility of using a somatic cell modeling system for defining the contribution proteins make to tumor development.

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    • "Given that p21 is a cyclin D-cdk4 assembly factor in the RCAS-PDGF-HA/nestin-TvA model [30], and TRIM3 can bind to p21 and suppress cell proliferation, we wanted to know if cyclin-cdks affected the interaction of TRIM3 and p21. We found that a mutant of p21 deficient in binding cyclin-cdk complexes bound better to TRIM3 than wild type p21 in extracts containing cyclin-cdk complexes (Fig. 8A). "
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    ABSTRACT: The TRIM family of genes is largely studied because of their roles in development, differentiation and host cell antiviral defenses; however, roles in cancer biology are emerging. Loss of heterozygosity of the TRIM3 locus in ∼20% of human glioblastomas raised the possibility that this NHL-domain containing member of the TRIM gene family might be a mammalian tumor suppressor. Consistent with this, reducing TRIM3 expression increased the incidence of and accelerated the development of platelet-derived growth factor -induced glioma in mice. Furthermore, TRIM3 can bind to the cdk inhibitor p21(WAF1/CIP1). Thus, we conclude that TRIM3 is a tumor suppressor mapping to chromosome 11p15.5 and that it might block tumor growth by sequestering p21 and preventing it from facilitating the accumulation of cyclin D1-cdk4.Oncogene advance online publication, 14 January 2013; doi:10.1038/onc.2012.596.
    Oncogene 01/2013; 33(3). DOI:10.1038/onc.2012.596 · 8.46 Impact Factor
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    • "Whether this role on leukemic stem cells is also related to the abnormal expression of proproliferative stemness factors including Sox2 remains unknown, but in favor of this view, SOX2 amplifications and altered expression have been found in human cancers that are not only of a brain origin (Bass et al., 2009; Maier et al., 2011). New oncogenic roles for cell cycle inhibitors are now being proposed (Besson et al., 2008) and, for example, PDGFinduced gliomagenesis is reduced in mice lacking p21 (Liu et al., 2007). To what extent p21 might be particularly important in safeguarding the genome of cancer stem cells in SOX2 overexpressing tumors is an interesting venue for future research. "
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    ABSTRACT: In the adult brain, continual neurogenesis of olfactory neurons is sustained by the existence of neural stem cells (NSCs) in the subependymal niche. Elimination of the cyclin-dependent kinase inhibitor 1A (p21) leads to premature exhaustion of the subependymal NSC pool, suggesting a relationship between cell cycle control and long-term self-renewal, but the molecular mechanisms underlying NSC maintenance by p21 remain unexplored. Here we identify a function of p21 in the direct regulation of the expression of pluripotency factor Sox2, a key regulator of the specification and maintenance of neural progenitors. We observe that p21 directly binds a Sox2 enhancer and negatively regulates Sox2 expression in NSCs. Augmented levels of Sox2 in p21 null cells induce replicative stress and a DNA damage response that leads to cell growth arrest mediated by increased levels of p19(Arf) and p53. Our results show a regulation of NSC expansion driven by a p21/Sox2/p53 axis.
    Cell stem cell 12/2012; 12(1). DOI:10.1016/j.stem.2012.12.001 · 22.27 Impact Factor
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    • "Additionally, it is hypothesized that p21 contains antiapoptotic activity and therefore, when overexpressed, damaged cells avoid degradation and proliferate to form tumors (Roninson, 2002). P21 might also promote cyclin D1 accumulation in the nucleus, therefore avoiding destruction, and facilitating binding with CDK4/6, leading to increased transcription (LaBaer et al., 1997; Liu et al., 2007). P21 has not been extensively studied in BE and EAC, but some evidence suggests that similar to p53 changes in the expression pattern of p21 may lead to a better response to treatment in these patients (Heeren et al., 2004). "
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