A Mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis.

By M. Adorno, M. Cordenonsi, Marco Montagner, S. Dupont, C. Wong, B. Hann, Aldo Solari, S. Bobisse, M. Rondina, V. Guzzardo and 5 more. Cell, 2009

728 citations recorded by the source corpus.

TGFbeta ligands act as tumor suppressors in early stage tumors but are paradoxically diverted into potent prometastatic factors in advanced cancers. The molecular nature of this switch remains enigmatic. Here, we show that TGFbeta-dependent cell migration, invasion and metastasis are empowered by mutant-p53 and opposed by p63. Mechanistically, TGFbeta acts in concert with oncogenic Ras and mutant-p53 to induce the assembly of a mutant-p53/p63 protein complex in which Smads serve as essential platforms. Within this ternary complex, p63 functions are antagonized. Downstream of p63, we identified two candidate metastasis suppressor genes associated with metastasis risk in a large cohort of breast cancer patients. Thus, two common oncogenic lesions, mutant-p53 and Ras, selected in early neoplasms to promote growth and survival, also prefigure a cellular set-up with particular metastasis proclivity by TGFbeta-dependent inhibition of p63 function.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/55691c27e6e7b176124c90801de75ec7ee413390

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Citations in the corpus

MicroRNA control of signal transduction (2010, background): “Mutations in p53 are frequent in cancer; these disable DNA recognition but lead to the gain of metastatic properties in response to signalling cues such as those transmitted by TGF&beta”
The regulation of TGFβ signal transduction (2009, background): “Interestingly, although Smads cooperate with wild-type p53 to promote developmental processes, they also cooperate with mutant p53, which often accumulates in human cancers (Adorno et al., 2009; Kalo et al., 2007).”
The ins and outs of the epithelial to mesenchymal transition in health and disease. (2011, background): “F or p er so na l u se o nl y. Oxidative stress: pathological changes seen in living organisms in response to excessive levels of cytotoxic oxidants and oxygen free radicals (Adorno et al. 2009).”
Mutant p53 gain-of-function in cancer. (2010, background): “The interaction between mutp53 and p63/ p73 can be regulated by cell-intrinsic and extrinsic signals and by additional partner proteins, as illustrated by the formation of a ternary complex between mutp53, p63, and Smad proteins, which is induced by TGF-b and oncogenic Ras (Adorno et al. 2009).”
Apoptosis, autophagy, necroptosis, and cancer metastasis (2015, neutral): “By interacting with mutant p53, p63 suppressed tumorigenesis and metastasis [53,54].”
p53 Proteoforms and Intrinsic Disorder: An Illustration of the Protein Structure–Function Continuum Concept (2016, background): “For example, the RAS-mediated phosphorylation of the Arg280Lys mutant of p53 at Ser6 and Ser9 promotes interaction of the mutated p53 with Smad, and the formation of this complex results in the inhibition of the antimetastasis activities of p63 [250].”
Inflammation and EMT: an alliance towards organ fibrosis and cancer progression (2009, background): “…the platelet-derived growth factor (PDGF) gene limits the proliferative or cytostatic effect of TGF-b1 in gliomas (Bruna et al, 2007) and the concerted action of TGF-b1 with oncogenic Ras and mutant p53 sequester p63 in a complex that inactivate its tumour suppressor effects (Adorno et al, 2009).”
Mutant p53 drives invasion by promoting integrin recycling. (2009, neutral): “After oncogenic stimulation such as expression of V12Ras or ErbB2 (NeuT) or coexpression of ErbB1 and TGF-b, these cells can be induced to form invasive structures (Muthuswamy et al., 2001; Seton-Rogers et al., 2004).”
Mutant p53: one name, many proteins. (2012, background): “…stem cell characteristics (Mizuno et al. 2010; Sarig et al. 2010), disruption of tissue architecture (Freed-Pastor et al. 2012), and angiogenesis (Fontemaggi et al. 2009), as well as migration, invasion, and metastasis (Hsiao et al. 1994; Adorno et al. 2009; Muller et al. 2009; Noll et al. 2011).”
TGFβ signalling: a complex web in cancer progression (2010, background): “Recent studies have shown that mutation of p53 is involved in this switching of TGFβ from a tumour suppressor to a tumour promote”
The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. (2011, methodology): “Immunoprecipitations were carried out as in Adorno et al. (2009), with the following modifications: extracts were diluted to 20 mM HEPES (pH 7.8), 100 mM NaCl, 5% glycerol, 2.5 mM MgCl2, 1% Triton X-100, 0.5% NP40 and incubated with protein A-sepharose-bound anti-TAZ/YAP monoclonal antibody (Santa…”