Functional analysis and molecular modeling show a preserved wild-type activity of p53(C238Y)
Authors: Marco A Pierotti
Elisa Pastore
Maria Silvia Paneni
Marco Ferrone
Domenico Delia
Sabrina Pricl
Maurizio Fermeglia
Federica Perrone
Silvana Pilotti
Elena Tamborini
Simona Suardi
Journal: Molecular Cancer Therapeutics (2006)
Discipline: CLINICAL MEDICINE
Keywords: p53; MDM2; missense mutation; transcription factor; gene amplification
Affiliations: Molecular Simulation Engineering Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy.

Abstract:  In human tumors, p53 is often disabled by mutations in its DNA-binding domain and is thus inactive as a transcription factor. Alternatively, MDM2 gene amplification or up-regulation represents a mechanism of p53 wild-type inactivation, mainly reported in soft tissue sarcomas. In a previous TP53 analysis carried out on sporadic and NF1-related malignant peripheral nerve sheath tumors, in two cases, we observed the occurrence of C238Y missense mutation, leading to p53 stabilization unexpectedly coupled with immunophenotypic MDM2 overexpression. To investigate this TP53 missense mutation not yet functionally characterized in mammalian cell, we did MDM2 Southern blot and p53(C238Y)/MDM2 biochemical and functional analyses followed by molecular modeling. The results showed a lack of MDM2 gene amplification, evidence of p53-MDM2 protein complexes, and presence of a p53 that retains the ability to become phosphorylated on Ser15 and to induce the transcription of p21(waf1). Additional molecular modeling data highlighted the structural similarities between p53(C238Y) and wild-type p53, further supporting that the p53(C238Y) mutant still retains functional wild-type p53 properties. 

Retracted: No

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 Via https: www.ilfattoquotidiano.it in-edicola articoli 2019 11 28 ricerche-mediche-aggiustate-pero-la-scienza-tace 5583974 (and Google translate) Fixed medical research, but science is silent by Gianni Barbacetto | NOVEMBER 28, 2019 u201cFor justice everything is fine. But is this okay for the scientific community ? Is it possible to falsify the images of the experiments, or avoid doing the control experiment, without anyone having anything to say? These are the questions that remain, at the end of a long judicial investigation by the Milan Public Prosecutor s Office on some articles of the most important Italian scientists engaged in cancer research. Professor Alberto Mantovani of Humanitas, Pier Giuseppe Pelicci of Ieo, Pier Paolo Di Fiore of Ifom, Marco Pierotti, with Maria Angela Greco, Elena Tamburini and Silvana Pilotti of the Cancer Institute, were investigated by prosecutors Francesco Cajani and Paolo Filippini for having manipulated the images of some of their studies published in international scientific journals. They are research luminaries who maneuver millions of euros from public funds, private donations, 5 per thousand collections . They received, only in the period analyzed by the Public Prosecutor (2005-2012), very high figures: 9.37 million Di Fiore; 3.06 Mantovani; 1.48 Pelicci; 3.60 Pierotti, for a total of 17 million paid by the CNR , the Ministry of Health and the University. And they got caught  fixing their research records. Now the judge of the preliminary investigation Sofia Fioretta has closed the investigation started in 2014, dismissing the accusations and arguing - with bold arguments - that the professors  did not carry out any falsification activities  . The two prosecutors had already requested the filing, arguing that the manipulations are established, but that the crime of  scientific fraud does not exist in Italy (as there is instead that of insurance fraud and sports fraud), therefore it is not possible pursue the behaviors of the seven excellent oncologists. The investigating judge was more creative : he recognized  a harmless and innocent fake , realized  because there was no time or money to perform the replication, or because competitors were coming first (what stupid scientists who do everything right instead ). Therefore,  insignificant errors were made . Replicas of the experiments were not carried out, but this  did not affect the content of the research and  did not undermine the scientific validity of the published thesis . In short: the luminaries were wrong, but in modest quantity . Yet the examinations of the experts of the Public Prosecutor s Office have ascertained the manipulations: three in the works of Pelicci-Ieo, four in those of the group of Pierotti-Istituto dei tumori (i.e. two by Pilotti and one by Greco and Tamburini), one in the works by Di Fiore-Ifom and one by Mantovani-Humanitas. But nothing wrong with that, that s okay, the investigating judge Fioretta reassures us. Closed the judicial game, at this point we ask some questions to the scientific community: 1. Are there, in scientific practice,  harmless and innocent false manipulations , but  of little significance ? 2. Is it normal that seven luminaries of oncology research publish images in international scientific journals that are manipulated in 21 out of 27 cases analyzed? 3. Is it compatible with the scientific method that, having performed the first experiment, one tarot the replica,  because there was no time or money to perform it,  or because competitors were arriving first ? 4. Since it is impossible, on the judicial level, to establish the direct connection between research carried out and funds obtained, is it still normal, on the scientific and ethical level, to obtain money, public and private, with the prestige gained (also) with fake research? 5. Is the scientific community sure that squaring up (corporately) and rejoicing in the  false innocents is the best way to defend science and the scientific method, now threatened by charlatans, scoundrels and no-vaxes?u201d ,