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)

Transforming growth factor-beta TGF-beta is the prototype for a family of extracellular proteins that affect cell proliferation and tissue differentiation. TGF-beta-related factors, including BMP-2/4, Dpp and activin, act through two types of serine/threonine kinase receptors which can form a heteromeric complex. However, the mechanism of signal transduction by these receptors is largely unknown. In Drosophila, Mad is required for signalling by Dpp. We have isolated complementary DNAs for four human Mad homologues, one of which, hMAD-4, is identical to DPC-4, a candidate tumour suppressor. hMAD-3 and -4 synergized to induce strong ligand-independent TGF-beta-like responses. When truncated at their carboxy termini, hMAD-3 and -4 act as dominant-negative inhibitors of the normal TGF-beta response. The activity of hMAD-3 and -4 was regulated by the TGF-beta receptors, and hMAD-3 but not hMAD-4 was phosphorylated and associated with the ligand-bound receptor complex. These results define hMAD-3 and -4 as effectors of the TGF-beta response and demonstrate a function for DPCA-4/hMAD-4 as a tumour suppressor.
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PMID:Receptor-associated Mad homologues synergize as effectors of the TGF-beta response. 877 81

The Smad4/DPC4 tumour suppressor is inactivated in nearly half of pancreatic carcinomas and to a lesser extent in a variety of other cancers. Smad4/DPC4, and the related tumour suppressor Smad2, belong to the SMAD family of proteins that mediate signalling by the TGF-beta/activin/BMP-2/4 cytokine superfamily from receptor Ser/Thr protein kinases at the cell surface to the nucleus. SMAD proteins, which are phosphorylated by the activated receptor, propagate the signal, in part, through homo- and hetero-oligomeric interactions. Smad4/DPC4 plays a central role as it is the shared hetero-oligomerization partner of the other SMADs. The conserved carboxy-terminal domains of SMADs are sufficient for inducing most of the ligand-specific effects, and are the primary targets of tumorigenic inactivation. We now describe the crystal structure of the C-terminal domain (CTD) of the Smad4/DPC4 tumour suppressor, determined at 2.5 A resolution. The structure reveals that the Smad4/DPC4 CTD forms a crystallographic trimer through a conserved protein-protein interface, to which the majority of the tumour-derived missense mutations map. These mutations disrupt homo-oligomerization in vitro and in vivo, indicating that the trimeric assembly of the Smad4/DPC4 CTD is critical for signalling and is disrupted by tumorigenic mutations.
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PMID:A structural basis for mutational inactivation of the tumour suppressor Smad4. 921 96

Colon cancer is a serious health problem, and novel preventive and therapeutical avenues are urgently called for. Delivery of proteins with anticancer activity through genetically modified bacteria provides an interesting, potentially specific, economic and effective approach here. Interestingly, bone morphogenetic protein 2 (BMP-2) is an important and powerful tumour suppressor in the colon and is thus an attractive candidate protein for delivery through genetically modified bacteria. It has not been shown, however, that BMP production in the bacterial context is effective on colon cancer cells. Here we demonstrate that transforming E. coli with a cDNA encoding an ileal-derived mature human BMP-2 induces effective apoptosis in an in vitro model system for colorectal cancer, whereas the maternal organism was not effective in this respect. Furthermore, these effects were sensitive to cotreatment with the BMP inhibitor Noggin. We propose that prevention and treatment of colorectal cancer using transgenic bacteria is feasible.
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PMID:E. coli-produced BMP-2 as a chemopreventive strategy for colon cancer: a proof-of-concept study. 2231 90