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 tumour suppressor APC is truncated in most colon cancers, which leads to the stabilization of beta-catenin and to the constitutive activation of Wnt signalling. However, it is not clear why colon cancer cells retain the truncated APC fragment. Here, we show that a decrease of APC levels achieved by RNA interference impairs cell proliferation and DNA replication, not only in 293 cells that express a wild-type protein, but also in SW480 colon cancer cells that express exclusively a truncated APC fragment. This correlates with a reduction of the levels of cyclin A, cyclin A-dependent kinase activity, p27(kip1) and the catalytic subunit of DNA polymerase delta. Thus, our data suggest that colon cancer cells retain a truncated APC fragment because it is essential for cell proliferation.
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PMID:Truncated APC is required for cell proliferation and DNA replication. 1645 Mar 83

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

JunB is a member of the AP-1 (activator protein-1) family of dimeric transcription factors. It exerts a dual action on the cell cycle. It is best known as a cell proliferation inhibitor, a senescence inducer and a tumour suppressor. As for the molecular mechanisms involved, they largely involve both positive actions on genes such as the p16INK4alpha cyclin-dependent kinase inhibitor and negative effects on genes such as cyclin D1 during the G1-phase of the cell cycle. However, JunB is also endowed with a cell-division-promoting activity, in particular via stimulation of cyclin A2 gene expression during S-phase. Strikingly, its role in G2 and M has received little attention so far despite its possible role in the preparation of mitosis. This review addresses the known and possible mechanisms whereby JunB is implicated in the control of the different phases of the cell cycle.
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PMID:Regulation and function of JunB in cell proliferation. 1879 52

Oligosaccharides are present in human milk in large amounts and in a high variety. We have previously shown that these oligosaccharides are strong inhibitors of proliferation and inducers of differentiation in intestinal cell lines. To elucidate the molecular mechanism, we investigated the influence on cell cycle events via flow cytometry and expression levels by using quantitative real-time RT-PCR. Human intestinal cells, i.e. HT-29, HIEC and Caco-2 cells, were exposed to neutral or acidic human milk oligosaccharides. Both fractions induced a concentration-dependent G2/M arrest. Cell cycle analysis for HT-29 revealed 37 % of cells in G1 and 35 % in G2/M (neutral oligosaccharides) and incubation with acidic oligosaccharides led to 42 % cells in G1 and 40 % in G2/M. In control experiments without oligosaccharides we found 71 % of cells to be in G1 and 17 % in G2/M. This G2/M arrest was associated with changes in mRNA expression of cyclin A and B. A G2/M arrest with concomitant alterations of cell cycle gene expression could also be shown for HIEC and Caco-2 cells. Analysing the expression of cyclin-dependent kinase inhibitors p21(cip1) and p27(kip1) and the tumour suppressor p53 we observed that the expression of p21(cip1) was p53-independent and necessary for arresting cells in the G2/M phase, while p27(kip1) was associated with differentiation effects. Both neutral and acidic human milk oligosaccharides were able to induce epidermal growth factor receptor, extracellular signal-regulated kinase 1/2 and p38 phosphorylation. These results suggest that oligosaccharides from human milk inhibited intestinal cell proliferation and altered cell cycle dynamics by affecting corresponding regulator genes and mitogen-activated protein kinase signalling.
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PMID:Oligosaccharides from human milk induce growth arrest via G2/M by influencing growth-related cell cycle genes in intestinal epithelial cells. 1907 36

Pseudokinases lack essential residues for kinase activity, yet are emerging as important regulators of signal transduction networks. The pseudokinase STRAD activates the LKB1 tumour suppressor by forming a heterotrimeric complex with LKB1 and the scaffolding protein MO25. Here, we describe the structure of STRADalpha in complex with MO25alpha. The structure reveals an intricate web of interactions between STRADalpha and MO25alpha involving the alphaC-helix of STRADalpha, reminiscent of the mechanism by which CDK2 interacts with cyclin A. Surprisingly, STRADalpha binds ATP and displays a closed conformation and an ordered activation loop, typical of active protein kinases. Inactivity is accounted for by nonconservative substitution of almost all essential catalytic residues. We demonstrate that binding of ATP enhances the affinity of STRADalpha for MO25alpha, and conversely, binding of MO25alpha promotes interaction of STRADalpha with ATP. Mutagenesis studies reveal that association of STRADalpha with either ATP or MO25alpha is essential for LKB1 activation. We conclude that ATP and MO25alpha cooperate to maintain STRADalpha in an "active" closed conformation required for LKB1 activation. It has recently been demonstrated that a mutation in human STRADalpha that truncates a C-terminal region of the pseudokinase domain leads to the polyhydramnios, megalencephaly, symptomatic epilepsy (PMSE) syndrome. We demonstrate this mutation destabilizes STRADalpha and prevents association with LKB1. In summary, our findings describe one of the first structures of a genuinely inactive pseudokinase. The ability of STRADalpha to activate LKB1 is dependent on a closed "active" conformation, aided by ATP and MO25alpha binding. Thus, the function of STRADalpha is mediated through an active kinase conformation rather than kinase activity. It is possible that other pseudokinases exert their function through nucleotide binding and active conformations.
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PMID:ATP and MO25alpha regulate the conformational state of the STRADalpha pseudokinase and activation of the LKB1 tumour suppressor. 1951 7

Breast cancer is a heterogeneous disease, and among all types, triple-negative breast cancer (TNBC) is characterised by high risk of recurrence. The discovery of microRNAs (miRNA) has opened the door for targeted therapy of TNBC. miR-340 down-regulation and sub-G1-accumulated cells in flowcytometry were observed in metastatic TNBC cells (data in publication), leading us to investigate the potential tumour suppressive role of this miRNA on cell-cycle-related genes. A lentiviral vector containing miR-340 was applied to over-express miR-340 in TNBC cell line, MDA-MB-231. Then, the expression of some cell-cycle-regulating genes including cyclin A2 (cyclin A2), Cyclin-dependent kinases 2 (CDK2), cyclin-dependent kinase inhibitors (P16, P18 and P27), Retinoblastoma (RB) and transcription factors (SMAD 4, SOX2 and SOX17) was investigated using quantitative RT-PCR. The results showed a decline in the expression of SOX2, P16 and P27 after miR-340 over-expression, whereas we observed an increase in the expression of cyclin A2, CDK2, SOX17, P18, SMAD 4 and RB. The over-expression of tumour suppressor genes such as RB and SOX17 and down-regulation of an oncogene such as SOX2 were in accordance to the inhibitory role of miR-340 that causes blockage of breast cancer metastasis which should be further investigated.
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PMID:The effect of miR-340 over-expression on cell-cycle-related genes in triple-negative breast cancer cells. 2722 58


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