Cytoplasmic gain-of-function mutant p53 contributes to inflammation-associated cancer

Inflammation and mutation of the tumor suppressor p53 are two apparently unrelated conditions that are strongly associated with cancer initiation and progression. We recently reported that gain-of-function mutant p53 modifies the response of cancer cells to inflammatory signals by binding a cytoplasmic tumor suppressor protein involved in TNFa signaling

Johann Carl Loth (1632-1698) : le rotte della geografia artistica di un pittore veneziano fra l'Italia e l'Europa germanofona

[estratto dall'intoduzione] In un percorso che si snoda parallelamente alla biografia dell\u2019artista viene restituita la mappatura della geografia artistica di Loth, attraverso la ricostruzione della trama dei rapporti che accompagnarono le principali commissioni soddisfatte dall\u2019artista e che connotarono i contesti di ricezione figurativa, collezionistica e storiografica delle sue opere. Sono state tracciate, pertanto, le interconnessioni fra le scelte linguistiche o stilistiche e di genere adottate da Loth nel corso della sua carriera e i diversi contesti culturali di ricezione delle medesime (Venezia e l\u2019entroterra veneto, l\u2019Impero austriaco, i territori germanici e Firenze). La risistemazione e la rivalutazione delle conoscenze oggettive della vicende dell\u2019artista e delle sue opere, debitrici del minuzioso lavoro di catalogazione condotto da Ewald, nonch\ue9 delle sue scoperte documentarie \u2013 le pi\uf9 rilevanti ancora sull\u2019artista \u2013, e che sono state puntigliosamente collazionate con i pi\uf9 recenti aggiornamenti (Fusari 2017), \ue8 stata condotta parallelamente a una disamina attenta delle principali fonti storiografiche e critiche tradizionali (Boschini e Sandrart, in primis), della letteratura periegetica, della corrispondenza fra mecenati, artisti e collezionisti, degli inventari delle raccolte o dei cataloghi a stampa e delle descrizioni letterarie. Si \ue8 provveduto, inoltre, a revisionare il materiale archivistico e documentario gi\ue0 pubblicato, accanto allo spoglio di ulteriori e inesplorati fondi. Una fase importante della ricerca \ue8 stata quindi dedicata ai sopralluoghi condotti presso svariate istituzioni museali o ecclesiastiche, utili sia per verificare l\u2019attuale reperibilit\ue0 del materiale menzionato nelle fonti, sia per approfondire gli aspetti della provenienza, della musealizzazione e della storia conservativa dei dipinti di Loth. [...

p73 as a Pharmaceutical Target for Cancer Therapy

About half of all human tumors contain an inactivating mutation of p53, while in the remaining tumors, the p53 pathway is frequently abrogated by alterations of other components of its signaling pathway. In humans, the p53 tumor suppressor is part of a small gene family that includes two other members, p73 and p63, structurally and functionally related to p53. Accumulating evidences indicate that all p53-family proteins function as molecular hubs of a highly interconnected signaling network that coordinates cell proliferation, differentiation and death in response to physiological inputs and oncogenic stress. Therefore, not only the p53-pathway but the entire “p53-family pathway” is a primary target for cancer drug development. In particular, the p53-related protein p73 has a crucial role in determining cellular responses to chemotherapy, and can vicariate p53 functions in triggering cell death after DNA damage in multiple experimental models. The biology and regulation of p73 is complex, since the TP73 gene incorporates both tumor-suppressive and proto-oncogenic functions. However, the p73 gene is rarely mutated in tumors, so appropriate pharmacological manipulation of the p73 pathway is a very promising approach for cancer therapy. Here we provide an overview of the principal mechanism of p73 regulation, and describe several examples of pharmacological tools that can induce p73 accumulation and function by acting on upstream p73 modulators or displacing inhibitory p73 interactors. A better understanding of how the p73 pathway works is mandatory to discover additional players intervening in this pathway and has important implications for the improvement of cancer treatment with the development of new molecules or with the reposition of currently available drugs

Ruokaan liittyvät bioteknologiat Italiassa : sosiaalipsykologinen tutkimus

This dissertation presents an analysis of the representations of food biotechnologies in Italy. The thesis uses the analysis of discourse to illustrate the articulated ways in which representations are instantiated in different contexts. The theoretical thrust of the work resides in its discussion of the basic tenets of both Social Representations Theory and Discursive Psychology. The thesis offers a detailed description of the two frameworks; affinities and difference are highlighted, and a serious effort is made to develop an integrated set of theoretical resources to answer the research questions. The thesis proposes to combine a discursive methodology with Social Representations Theory. After a description of the relevant legislative framework follows an illustration of the categories used for the textual analysis. The study proposes the textual analysis of the following data: the first declaration issued by a small Italian council rejecting biotechnologies; four texts which focus on positions taken by the Catholic Church in the matter of food biotechnologies; several transcripts from a public debate in a small community of the north west of Italy. The latter study, which included an ethnographic dimension, focuses on recordings from interviews, a focus group, a public meeting and newspaper articles. Particular attention is paid to ideological representations and to the relevance of citizenship and governance to debates about food biotechnologies.Ruokaan liittyvät bioteknologiat Italiassa: sosiaalipsykologinen tutkimus Väitöskirjassa esitetään analyysi ruokaan liittyvien bioteknologioiden representaatioista Italiassa. Työssä käytetään keskustelujen analyysejä kuvaamaan niitä artikuloituja tapoja, joilla representaatioita ilmennetään erilaisissa konteksteissa. Työn teoreettinen anti perustuu sosiaalisten representaatioiden teorian ja diskursiivisen psykologian teorian perusteiden käsittelylle. Väitöskirja tarjoaa yksityiskohtaisen kuvauksen kummastakin viitekehyksestä; yhtäläisyydet ja erot tuodaan esille. Pyrkimyksenä on kehittää integroidut teoreettiset resurssit, joiden avulla voidaan vastata tutkimuskysymyksiin. Työssä yhdistetään diskursiivinen metodologia sosiaalisten representaatioiden teoriaan. Relevantin lainsäädännöllisen viitekehyksen kuvauksen jälkeen seuraa tekstuaalisessa analyysissä käytettyjen kategorioiden kuvaus. Työssä analysoidaan seuraavat materiaalit: ensimmäinen virallinen pienen italialaisen valtuuston esittämä bioteknologian torjuva julkilausuma; neljä tekstiä, joissa keskitytään katolisen kirkon esittämiin bioteknologiaa koskeviin kantoihin; useita tekstinäytteitä julkisesta keskustelusta pienessä kylässä Koillis-Italiassa. Viimeksi mainittu tutkimus, johon sisältyi etnografinen ulottuvuus, keskittyy haastateltuihin nauhoituksiin, fokusryhmään, julkiseen kokoukseen ja sanomalehtiartikkeleihin. Erityistä huomiota kiinnitetään ideologisiin representaatioihin ja kansalaisuuden ja hallitsemisen merkityksellisyyteen bioteknologiaa koskevissa keskusteluissa

A mechanism for cell non-autonomous inactivation of the tumor suppressor DAB2IP

no abstrac

Wild-type and mutant p53 in cancer-related ferroptosis. A matter of stress management?

Cancer cells within tumor masses are chronically exposed to stress caused by nutrient deprivation, oxygen limitation, and high metabolic demand. They also accumulate hundreds of mutations, potentially generating aberrant proteins that can induce proteotoxic stress. Finally, cancer cells are exposed to various damages during chemotherapy. In a growing tumor, transformed cells eventually adapt to these conditions, eluding the death-inducing outcomes of signaling cascades triggered by chronic stress. One such extreme outcome is ferroptosis, a form of iron-dependent non-apoptotic cell death mediated by lipid peroxidation. Not surprisingly, the tumor suppressor p53 is involved in this process, with evidence suggesting that it acts as a pro-ferroptotic factor and that its ferroptosis-inducing activity may be relevant for tumor suppression. Missense alterations of the TP53 gene are extremely frequent in human cancers and give rise to mutant p53 proteins (mutp53) that lose tumor suppressive function and can acquire powerful oncogenic activities. This suggests that p53 mutation provides a selective advantage during tumor progression, raising interesting questions on the impact of p53 mutant proteins in modulating the ferroptotic process. Here, we explore the role of p53 and its cancer-related mutants in ferroptosis, using a perspective centered on the resistance/sensitivity of cancer cells to exogenous and endogenous stress conditions that can trigger ferroptotic cell death. We speculate that an accurate molecular understanding of this particular axis may improve cancer treatment options

The Transcriptional Repressor hDaxx Potentiates p53-dependent Apoptosis

p53 and its homologues p73 and p63 are transcription factors that play an essential role in modulating cell cycle arrest and cell death in response to several environmental stresses. The type and intensity of these responses, which can be different depending on the inducing stimulus and on the overall cellular context, are believed to rely on the activation of defined subsets of target genes. The proper activation of p53 family members requires the coordinated action of post-translational modifications and interaction with several cofactors. In this study, we demonstrate that the multifunctional protein hDaxx interacts with p53 and its homologues, both in vitro and in vivo, and modulates their transcriptional activity. Moreover, we show that hDaxx, which has been implicated in several apoptotic pathways, increases the sensitivity to DNA damage-induced cell death and that this effect requires the presence of p53. Although hDaxx represses p53-dependent transcription of the p21 gene, it does not affect the activation of proapoptotic genes, and therefore acts by influencing the balance between cell cycle arrest and proapoptotic p53 targets. Our results therefore underline the central role of hDaxx in modulating the apoptotic threshold upon several stimuli and identify it as a possible integrating factor that coordinates the response of p53 family members

Mutant p53 improves cancer cells\u2019 resistance to endoplasmic reticulum stress by sustaining activation of the UPR regulator ATF6

Missense mutations in the TP53 gene are frequent in human cancers, giving rise to mutant p53 proteins that can acquire oncogenic properties. Gain of function mutant p53 proteins can enhance tumour aggressiveness by promoting cell invasion, metastasis and chemoresistance. Accumulating evidences indicate that mutant p53 proteins can also modulate cell homeostatic processes, suggesting that missense p53 mutation may increase resistance of tumour cells to intrinsic and extrinsic cancer-related stress conditions, thus offering a selective advantage. Here we provide evidence that mutant p53 proteins can modulate the Unfolded Protein Response (UPR) to increase cell survival upon Endoplasmic Reticulum (ER) stress, a condition to which cancer cells are exposed during tumour formation and progression, as well as during therapy. Mechanistically, this action of mutant p53 is due to enhanced activation of the pro-survival UPR effector ATF6, coordinated with inhibition of the pro-apoptotic UPR effectors JNK and CHOP. In a triple-negative breast cancer cell model with missense TP53 mutation, we found that ATF6 activity is necessary for viability and invasion phenotypes. Together, these findings suggest that ATF6 inhibitors might be combined with mutant p53-targeting drugs to specifically sensitise cancer cells to endogenous or chemotherapy-induced ER stress

Complexes formed by mutant p53 and their roles in breast cancer

Breast cancer is the most frequently diagnosed malignancy in women, and mutations in the tumor suppressor p53 are commonly detected in the most aggressive subtypes. The majority of TP53 gene alterations are missense substitutions, leading to expression of mutant forms of the p53 protein that are frequently detected at high levels in cancer cells. P53 mutants not only lose the physiological tumor-suppressive activity of the wild-type p53 protein but also acquire novel powerful oncogenic functions, referred to as gain of function, that may actively confer a selective advantage during tumor progression. Some of the best-characterized oncogenic activities of mutant p53 are mediated by its ability to form aberrant protein complexes with other transcription factors or proteins not directly related to gene transcription. The set of cellular proteins available to interact with mutant p53 is dependent on cell type and extensively affected by environmental signals, so the prognostic impact of p53 mutation is complex. Specific functional interactions of mutant p53 can profoundly impact homeostasis of breast cancer cells, reprogramming gene expression in response to specific extracellular inputs or cell-intrinsic conditions. The list of protein complexes involving mutant p53 in breast cancer is continuously growing, as is the number of oncogenic phenotypes in which they could be involved. In consideration of the functional impact of such complexes, key interactions of mutant p53 may be exploited as potential targets for development of therapies aimed at defusing the oncogenic potential of p53 mutation

Induction in myeloid leukemic cells of genes that are expressed in different normal tissues

Using DNA microarray and cluster analysis of expressed genes in a cloned line (M1-t-p53) of myeloid leukemic cells, we have analyzed the expression of genes that are preferentially expressed in different normal tissues. Clustering of 547 highly expressed genes in these leukemic cells showed 38 genes preferentially expressed in normal hematopoietic tissues and 122 other genes preferentially expressed in different normal non-hematopoietic tissues including neuronal tissues, muscle, liver and testis. We have also analyzed the genes whose expression in the leukemic cells changed after activation of wild-type p53 and treatment with the cytokine interleukin 6 (IL-6) or the calcium mobilizer thapsigargin (TG). Out of 620 such genes in the leukemic cells that were differentially expressed in normal tissues, clustering showed 80 genes that were preferentially expressed in hematopoietic tissues and 132 genes in different normal non-hematopietic tissues that also included neuronal tissues, muscle, liver and testis. Activation of p53 and treatment with IL-6 or TG induced different changes in the genes preferentially expressed in these normal tissues. These myeloid leukemic cells thus express genes that are expressed in normal non-hematopoietic tissues, and various treatments can reprogram these cells to induce other such non-hematopoietic genes. The results indicate that these leukemic cells share with normal hematopoietic stem cells the plasticity of differentiation to different cell types. It is suggested that this reprogramming to induce in malignant cells genes that are expressed in different normal tissues may be of clinical value in therapy