1,720,981 research outputs found
Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer
No full textOne of the most defining features of cancer is aberrant cell communication; therefore, a molecular understanding of the intricate network established among tumor cells and their microenvironment could significantly improve comprehension and clinical management of cancer. The tumor suppressor DAB2IP (Disabled homolog 2 interacting protein), also known as AIP1 (ASK1 interacting protein), has an important role in this context, as it modulates signal transduction by multiple inflammatory cytokines and growth factors. DAB2IP is a Ras-GAP, and negatively controls Ras-dependent mitogenic signals. In addition, acting as a signaling adaptor, DAB2IP modulates other key oncogenic pathways, including TNFα/NF-κB, WNT/β-catenin, PI3K/AKT, and androgen receptors. Therefore, DAB2IP inactivation can provide a selective advantage to tumors initiated by a variety of driver mutations. In line with this role, DAB2IP expression is frequently impaired by methylation in cancer. Interestingly, recent studies reveal that tumor cells can employ other sophisticated mechanisms to disable DAB2IP at the post-transcriptional level. We review the mechanisms and consequences of DAB2IP inactivation in cancer, with the purpose to support and improve research aimed to counteract such mechanisms. We suggest that DAB2IP reactivation in cancer cells could be a strategy to coordinately dampen multiple oncogenic pathways, potentially limiting progression of a wide spectrum of tumors.Cell Death and Differentiation advance online publication, 18 November 2016; doi:10.1038/cdd.2016.134
Cytoplasmic gain-of-function mutant p53 contributes to inflammation-associated cancer
Full text linkInflammation 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
The evolutionary conserved gene C16orf35 encodes a nucleo-cytoplasmic protein that interacts with p73
No full textC16orf35 is a highly conserved gene positioned upstream of the alpha-globins in humans and other vertebrates. The deduced protein is also highly conserved, it has no defined structural features or domains, and its function is currently unknown. Here we show that the C16orf35 protein has nuclear and cytosolic distribution, and can localize to PML nuclear bodies. The C16orf35 protein was detected in several human transformed cells lines, and studies of transient and stable overexpression indicate that increased levels of C16orf35 inhibit cell proliferation. We also find that C16orf35 interacts with human p73, and represses transcription by TAp73gamma but not by TAp73alpha. This selectivity is not due to differential interaction, since C16orf35 binds both p73 variants. Our data suggest that C16orf35 can modulate differentially the specific activities of selected p73 isoform
A genome-scale protein interaction profile of Drosophila p53 uncovers additional nodes of the human p53 network
No full textThe genome of the fruitfly Drosophila melanogaster contains a single p53-like protein, phylogenetically related to the ancestor of the mammalian p53 family of tumor suppressors. We reasoned that a comprehensive map of the protein interaction profile of Drosophila p53 (Dmp53) might help identify conserved interactions of the entire p53 family in man. Using a genome-scale in vitro expression cloning approach, we identified 91 previously unreported Dmp53 interactors, considerably expanding the current Drosophila p53 interactome. Looking for evolutionary conservation of these interactions, we tested 41 mammalian orthologs and found that 37 bound to one or more p53-family members when overexpressed in human cells. An RNAi-based functional assay for modulation of the p53 pathway returned five positive hits, validating the biological relevance of these interactions. One p53 interactor is GTPBP4, a nucleolar protein involved in 60S ribosome biogenesis. We demonstrate that GTPBP4 knockdown induces p53 accumulation and activation in the absence of nucleolar disruption. In breast tumors with wild-type p53, increased expression of GTPBP4 correlates with reduced patient survival, emphasizing a potential relevance of this regulatory axis in cancer
Functional analysis of novel interactors of mammalian p53 and p53-related proteins
Full text link2010/2011The tumor suppressor p53 plays a central role in the protection against DNA damage and other forms of stress, primarily by inducing cell cycle arrest or apoptosis. Mutation of p53, which is one of the most frequent genetic alterations detected in human cancers, inactivates these growth regulatory functions; in addition, very often mutant p53 acquires tumor-promoting activities (gain-of-function). A complete and thorough understanding of the signaling circuitry that regulates wild-type and mutant p53 functions is therefore a primary objective for basic cancer research, since it may lead to development of important tools for diagnosis and therapy of tumors. One crucial component of such knowledge is the protein interaction profile of p53.
To gain novel insights on p53 interactions, we used a phylogenetic approach. We reasoned that a comprehensive map of the protein interaction profile of Drosophila p53 might reveal conserved interactions of the entire p53 family in man. Using a genome-scale in vitro expression cloning approach, we identified 91 previously unreported Dmp53 interactors. Next, we studied and characterized the interaction of human orthologs of newly identified Dmp53 interactors with all p53-family proteins, and it resulted in the identification of several novel interactants of this family of tumor suppressors (Part 1 of this Thesis).
In parallel, we verified that many of the mammalian orthologs of Dmp53 interactors could also bind to an oncogenic p53 mutant (R175H), and therefore are potential novel targets or effectors of mut-53 gain of function activities. Among those proteins we focused our attention on DAB2IP, a tumor-suppressor gene that functions by counteracting the activation of multiple oncogenic pathways. There are evidences that mutant p53 has a stimulatory role in all the signaling pathways that are normally inhibited by DAB2IP; therefore, we propose that mutant p53 may bind and functionally inactivate DAB2IP as one of the mechanisms of its gain-of-function. Given the crucial role of DAB2IP in modulating cellular responses to TNF, we focus on the potential relevance of this interaction in the connection between inflammation and cancer (Part 2 of this Thesis).XXIII Ciclo198
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