1,721,006 research outputs found
A mechanism for cell non-autonomous inactivation of the tumor suppressor DAB2IP
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The secreted Frizzled-related protein Sizzled functions as a negative feedback regulator of extreme ventral mesoderm
No full textThe prevailing model of dorsal ventral patterning of the amphibian embryo predicts that the prospective mesoderm is regionalized at gastrulation in response to a gradient of signals. This gradient is established by diffusible BMP and Wnt inhibitors secreted dorsally in the Spemann organizer. An interesting question is whether ventrolateral tissue passively reads graded levels of ventralizing signals, or whether local self-organizing regulatory circuits may exist on the ventral side to control cell behavior and differentiation at a distance from the Organizer. We provide evidence that sizzled, a secreted Frizzled-related protein expressed ventrally during and after gastrulation, functions in a negative feedback loop that limits allocation of mesodermal cells to the extreme ventral fate, with direct consequences for morphogenesis and formation of the blood islands. Morpholino-mediated knockdown of Sizzled protein results in expansion of ventral posterior mesoderm and the ventral blood islands, indicating that this negative regulation is required for proper patterning of the ventral mesoderm. The biochemical activity of sizzled is apparently very different from that of other secreted Frizzled-related proteins, and does not involve inhibition of Wnt8. Our data are consistent with the existence of some limited self-organizing properties of the extreme ventral mesoderm
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
Cutting the Brakes on Ras - Cytoplasmic GAPs as Targets of Inactivation in Cancer
Full text linkThe 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
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
A novel p53-inducible gene encoding for a microtubule-localised protein with G2-specific expression
No full textThe rebel angel: Mutant p53 as the driving oncogene in breast cancer.
No full textBreast cancer is the most frequent invasive tumor diagnosed in women, causing over 400 thousand deaths yearly worldwide. Like other tumors, it is a disease of a complex, heterogeneous genetic and biochemical background. No single genomic or metabolic condition can be regarded as decisive for its formation and progression. However, a few key players can be pointed out and among them the TP53 tumor suppressor gene, being commonly mutated in breast cancer. In particular, TP53 mutations are exceptionally frequent and apparently among the key driving factors in the triple negative breast cancer (TNBC) - the most aggressive breast cancer subgroup whose management still represents a clinical challenge. The majority of TP53 mutations result in the substitution of single aminoacids in the central region of the p53 protein, generating a spectrum of variants ("mutant p53" for short). These mutants lose to various extent the normal p53 oncosuppressive functions, but can also acquire oncogenic properties by gain-of-function (GOF) mechanisms.This review discusses the molecular processes translating gene mutations to the pathologic consequences of mutant p53 tumorigenic activity, reconciling cell and animal models with clinical outcomes in breast cancer. Existing and speculative therapeutic methods targeting mutant p53 are also discussed, taking into account the overlap of mutant and wild-type (wt) p53 regulatory mechanisms and the crosstalk between mutant p53 and other oncogenic pathways in breast cancer. The studies described here concern breast cancer models and patients - unless it is indicated otherwise and justified by the importance of data obtained in other models
An update on the tumor-suppressive functions of the RasGAP protein DAB2IP with focus on therapeutic implications
Full text linkThe dynamic crosstalk between tumor and stromal cells is a major determinant of cancer aggressiveness. The tumor-suppressor DAB2IP (Disabled homolog 2 interacting protein) plays an important role in this context, since it modulates cell responses to multiple extracellular inputs, including inflammatory cytokines and growth factors. DAB2IP is a RasGAP and negatively controls Ras-dependent mitogenic signals. In addition, it modulates other major oncogenic pathways, including TNFα/NF-κB, WNT/β-catenin, PI3K/AKT, and androgen receptor signaling. In line with its tumor-suppressive role, DAB2IP is frequently inactivated in cancer by transcriptional and post-transcriptional mechanisms, including promoter methylation, microRNA-mediated downregulation, and protein-protein interactions. Intriguingly, some observations suggest that downregulation of DAB2IP in cells of the tumor stroma could foster establishment of a pro-metastatic microenvironment. This review summarizes recent insights into the tumor-suppressive functions of DAB2IP and the consequences of its inactivation in cancer. In particular, we explore potential approaches aimed at reactivating DAB2IP, or augmenting its expression levels, as a novel strategy in cancer treatment. We suggest that reactivation or upregulation of DAB2IP would concurrently attenuate multiple oncogenic pathways in both cancer cells and the tumor microenvironment, with implications for improved treatment of a broad spectrum of tumors
KeePin’ the p53 family in good shape.
No full textThe tumor suppressor p53 and the prolyl isomerase Pin1 are both highly connected proteins, lying at the crossroads between many signaling pathways that control cell proliferation and transformation. By catalyzing conformational changes in a large number of phosphorylated proteins, Pin1 has been implicated in the regulation of major cellular events, such as cell cycle progression, transcription, proliferation and differentiation. Recently, a role for Pin1 has emerged also in the DNA damage response, through modulation of p53 functions upon genotoxic stress. A further level of control has now been unveiled by showing that also the p53 sibling p73 requires Pin1 for its apoptotic activity
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