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

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

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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

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

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

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

Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat.

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Parkinson's Disease DJ-1 L166P Alters rRNA Biogenesis by Exclusion of TTRAP from the Nucleolus and Sequestration into Cytoplasmic Aggregates via TRAF6

Mutations in PARK7/DJ-1 gene are associated to autosomal recessive early onset forms of Parkinson's disease (PD). Although large gene deletions have been linked to a loss-of-function phenotype, the pathogenic mechanism of missense mutations is less clear. The L166P mutation causes misfolding of DJ-1 protein and its degradation. L166P protein may also accumulate into insoluble cytoplasmic aggregates with a mechanism facilitated by the E3 ligase TNF receptor associated factor 6 (TRAF6). Upon proteasome impairment L166P activates the JNK/p38 MAPK apoptotic pathway by its interaction with TRAF and TNF Receptor Associated Protein (TTRAP). When proteasome activity is blocked in the presence of wild-type DJ-1, TTRAP forms aggregates that are localized to the cytoplasm or associated to nucleolar cavities, where it is required for a correct rRNA biogenesis. In this study we show that in post-mortem brains of sporadic PD patients TTRAP is associated to the nucleolus and to Lewy Bodies, cytoplasmic aggregates considered the hallmark of the disease. In SH-SY5Y neuroblastoma cells, misfolded mutant DJ-1 L166P alters rRNA biogenesis inhibiting TTRAP localization to the nucleolus and enhancing its recruitment into cytoplasmic aggregates with a mechanism that depends in part on TRAF6 activity. This work suggests that TTRAP plays a role in the molecular mechanisms of both sporadic and familial PD. Furthermore, it unveils the existence of an interplay between cytoplasmic and nucleolar aggregates that impacts rRNA biogenesis and involves TRAF6

Mutant p53 as a guardian of the cancer cell

Forty years of research have established that the p53 tumor suppressor provides a major barrier to neoplastic transformation and tumor progression by its unique ability to act as an extremely sensitive collector of stress inputs, and to coordinate a complex framework of diverse effector pathways and processes that protect cellular homeostasis and genome stability. Missense mutations in the TP53 gene are extremely widespread in human cancers and give rise to mutant p53 proteins that lose tumor suppressive activities, and some of which exert trans-dominant repression over the wild-type counterpart. Cancer cells acquire selective advantages by retaining mutant forms of the protein, which radically subvert the nature of the p53 pathway by promoting invasion, metastasis and chemoresistance. In this review, we consider available evidence suggesting that mutant p53 proteins can favor cancer cell survival and tumor progression by acting as homeostatic factors that sense and protect cancer cells from transformation-related stress stimuli, including DNA lesions, oxidative and proteotoxic stress, metabolic inbalance, interaction with the tumor microenvironment, and the immune system. These activities of mutant p53 may explain cancer cell addiction to this particular oncogene, and their study may disclose tumor vulnerabilities and synthetic lethalities that could be exploited for hitting tumors bearing missense TP53 mutations

Cutting the Brakes on Ras - Cytoplasmic GAPs as Targets of Inactivation in Cancer

The Ras pathway is frequently deregulated in cancer, actively contributing to tumor development and progression. Oncogenic activation of the Ras pathway is commonly due to point mutation of one of the three Ras genes, which occurs in almost one third of human cancers. In the absence of Ras mutation, the pathway is frequently activated by alternative means, including the loss of function of Ras inhibitors. Among Ras inhibitors, the GTPase-Activating Proteins (RasGAPs) are major players, given their ability to modulate multiple cancer-related pathways. In fact, most RasGAPs also have a multi-domain structure that allows them to act as scaffold or adaptor proteins, affecting additional oncogenic cascades. In cancer cells, various mechanisms can cause the loss of function of Ras inhibitors; here, we review the available evidence of RasGAP inactivation in cancer, with a specific focus on the mechanisms. We also consider extracellular inputs that can affect RasGAP levels and functions, implicating that specific conditions in the tumor microenvironment can foster or counteract Ras signaling through negative or positive modulation of RasGAPs. A better understanding of these conditions might have relevant clinical repercussions, since treatments to restore or enhance the function of RasGAPs in cancer would help circumvent the intrinsic difficulty of directly targeting the Ras protein