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)

The proteasome constitutes the central proteolytic component of the highly conserved ubiquitin-proteasome system, which is required for the maintenance and regulation of basic cellular processes, including differentiation, proliferation, cell cycling, gene transcription and apoptosis. Here we show that inhibition of proteasomal proteolytic activity by the proteasome inhibitors bortezomib and lactacystin suppresses essential immune functions of human CD4(+) T cells activated by allogeneic dendritic cells (DCs). In activated CD4(+) T cells, proteasome inhibition induces apoptosis accompanied by rapid accumulation and stabilization of the tumour suppressor protein p53. Activated CD4(+) T cells surviving proteasome inhibition undergo inhibition of proliferation by induction of G(1) phase cell-cycle arrest. Induction of G(1) arrest is accompanied by the accumulation of cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and p27(KIP1) and the disappearance of cyclin A, cyclin D2 and proliferating cell nuclear antigen, proteins known to regulate G(1) to S phase cell-cycle transitions. Expression of the activation-associated cell surface receptors CD25, CD28, CD120b and CD134 as well as production of interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), interleukin-4 (IL-4) and IL-5 is suppressed in response to proteasome inhibition in CD4(+) T cells activated by DCs. Expression of CD25, IFN-gamma, TNF-alpha, IL-4 and IL-5 is known to be mediated by the transcriptional activity of nuclear factor of activated T cells (NFAT), and we show here that proteasome inhibition suppresses activation and nuclear translocation of NFATc2 in activated CD4(+) T cells. Thus, the proteasome is required for essential immune functions of activated CD4(+) T cells and can be defined as a molecular target for the suppression of deregulated and unwanted T-cell-mediated immune responses.
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PMID:Proteasome inhibition suppresses essential immune functions of human CD4+ T cells. 1821 57

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