Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell death plays an important role in regulating cell numbers in a wide variety of tissues during development and throughout life. Cell death can be triggered by changes in the levels of hormones and growth factors and is regulated by the expression of the tumour suppressor gene p53 in many cells. To determine if p53 plays a role in neuronal death resulting from neurotrophin deprivation, we studied the survival of neurons obtained from normal mouse embryos and embryos with a null mutation in the p53 gene. Embryonic sensory and sympathetic neurons from mutant embryos survived in response to the appropriate neurotrophin and died normally in the absence of neurotrophins. These results indicate that neurotrophin-deprived neurons die by a p53-independent pathway.
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PMID:Neurons from mouse embryos with a null mutation in the tumour suppressor gene p53 undergo normal cell death in the absence of neurotrophins. 789 74

Distinct changes in glycogen synthase kinase-3 (GSK-3) signalling can regulate neuronal morphogenesis including the determination and maintenance of axonal identity, and are required for neurotrophin-mediated axon elongation. In addition, we have previously shown a dependency on GSK-3 activation in the semaphorin 3A (Sema3A)-mediated growth-cone-collapse response of sensory neurons. Regulation of GSK-3 activity involves the intermediate signalling lipid phosphatidylinositol 3,4,5-trisphosphate, which can be modulated by phosphatidylinositol 3-kinase (PI3K) and the tumour suppressor PTEN. We report here the involvement of PTEN in the Sema3A-mediated growth cone collapse. Sema3A suppresses PI3K signalling concomitant with the activation of GSK-3, which depends on the phosphatase activity of PTEN. PTEN is highly enriched in the axonal compartment and the central domain of sensory growth cones during axonal extension, where it colocalises with microtubules. Following exposure to Sema3A, PTEN accumulates rapidly at the growth cone membrane suggesting a mechanism by which PTEN couples Sema3A signalling to growth cone collapse. These findings demonstrate a dependency on PTEN to regulate GSK-3 signalling in response to Sema3A and highlight the importance of subcellular distributions of PTEN to control growth cone behaviour.
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PMID:PTEN couples Sema3A signalling to growth cone collapse. 1649 86

By screening a fetal brain two-hybrid library with the death domain of the p75 neurotrophin receptor (NTR), we identified the Sall2 transcription factor as a novel interacting protein. Sall2 is a unique member of the Sall gene family, which is believed to be a tumour suppressor. Here, we show that Sall2 contains a p75NTR interaction domain not found in other Sall proteins and that p75NTR/Sall2 complexes co-immunoprecipitate from brain lysates. NGF dissociates p75NTR/Sall2 complexes and activates TrkA, which has an obligate function in the nuclear translocation of Sall2. NGF also increases Sall2 expression and this is mediated by p75NTR, but may not require TrkA. Depletion of Sall2 from cells decreases the expression and activity of p21(WAF1/CIP1), as well as the ability of NGF to induce growth arrest and the development of neurites. Overexpression of Sall2 activates p21(WAF1/CIP1), induces growth arrest, and promotes neurite outgrowth independently of NGF. These data establish Sall2 as a link between NTRs and transcriptional events that regulate the growth and development of neuronal cells.
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PMID:Sall2 is a novel p75NTR-interacting protein that links NGF signalling to cell cycle progression and neurite outgrowth. 1913 67

Hsp90 chaperones stabilize many tyrosine kinases including several oncogenes, which are inhibited or induced to degrade by the Hsp90 inhibitor geldanamycin (GA). As a consequence, GA has been developed for future chemotherapeutic use in several tumour types including neuroblastoma (NB). Alternative splicing of the neurotrophin receptor tyrosine kinase TrkA may have a pivotal function in regulating NB behaviour, with reports suggesting that tumour-suppressing signals from TrkA may be converted to oncogenic signals by stress-regulated alternative TrkAIII splicing. Within this context, it is important to know whether Hsp90 interacts with TrkA variants in NB cells and how GA influences this. Here, we report that both TrkAI and TrkAIII are Hsp90 clients in human NB cells. TrkAI exhibits GA-sensitive interaction with Hsp90 required for receptor endoplasmic reticulum export, maturation, cell surface stabilization and ligand-mediated activation, whereas TrkAIII exhibits GA-sensitive interactions with Hsp90 required for spontaneous activity and to a lesser extent stability. We show that GA inhibits proliferation and induces apoptosis of TrkAI expressing NB cells, whereas TrkAIII reduces the sensitivity of NB cells to GA-induced elimination. Our data suggest that GA-sensitive interactions with Hsp90 are critical for both TrkAI tumour suppressor and TrkAIII oncogenic function in NB and that TrkAIII expression exerts a negative impact on GA-induced NB cell eradication, which can be counteracted by a novel TrkAIII-specific peptide nucleic acid inhibitor.
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PMID:The neuroblastoma tumour-suppressor TrkAI and its oncogenic alternative TrkAIII splice variant exhibit geldanamycin-sensitive interactions with Hsp90 in human neuroblastoma cells. 1973 38

Oncogenes derived from the neurotrophin receptor tropomyosin-related kinase TrkA act as drivers in sub-populations of a wide-range of human cancers. This, combined with a recent report that both adult and childhood cancers driven by novel oncogenic TrkA chimeric-fusions exhibit profound, long-lived therapeutic responses to the Trk inhibitor Larotrectinib, highlights the need to improve clinical detection of TrkA oncogene-driven cancers in order to maximise this novel therapeutic potential. Cancers potentially driven by TrkA oncogenes include a proportion of paediatric neuroblastomas (NBs) that express the alternative TrkA splice variant TrkAIII, which exhibits exon 6, 7 and 9 skipping and oncogenic-activity that depends upon deletion of the extracellular D4 Ig-like domain. In contrast to fully spliced TrkA, which exhibits tumour suppressor activity in NB and associates with good prognosis, TrkAIII associates with advanced stage metastatic disease, post therapeutic relapse and worse prognosis, induces malignant transformation of NIH-3T3 cells and exhibits oncogenic activity in NB models. TrkAIII induction in NB cells is stress-regulated by conditions that mimic hypoxia or perturbate the ER with potential to change TrkA tumour-suppressing signals into oncogenic TrkAIII signals within the stressful tumour microenvironment. In contrast to cell surface TrkA, TrkAIII re-localises to intracellular pre-Golgi membranes, centrosomes and mitochondria, within which it exhibits spontaneous ligand-independent activation, triggering a variety of mechanisms that promote tumorigenicity and malignant behaviour, which impact the majority of cancer hallmarks. In this review, we present updates on TrkAIII detection and association with human malignancies, the multiple ways TrkAIII exerts oncogenic activity and potential therapeutic approaches for TrkAIII expressing cancers, with particular reference to NB.
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PMID:The oncogenic neurotrophin receptor tropomyosin-related kinase variant, TrkAIII. 2991 59