Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cyclin-dependent kinase (CDK) inhibitor p27 is degraded at the G(0)-G(1) transition of the cell cycle by the ubiquitin-proteasome pathway in a Skp2-independent manner. We recently identified a novel ubiquitin ligase, KPC (Kip1 ubiquitylation-promoting complex), consisting of KPC1 and KPC2, which regulates the ubiquitin-dependent degradation of p27 at G(1) phase. We have now investigated the structural requirements for the interactions of KPC1 with KPC2 and p27. The NH(2)-terminal region of KPC1 was found to be responsible for binding to KPC2 and to p27. KPC1 mutants that lack this region failed to mediate polyubiquitylation of p27 in vitro and expression of one such mutant delayed p27 degradation in vivo. We also generated a series of deletion mutants of p27 and found that KPC failed to polyubiquitylate a p27 mutant that lacks the CDK inhibitory domain. Interestingly, the cyclin E.CDK2 complex prevented both the interaction of KPC with p27 as well as KPC-mediated polyubiquitylation of p27. A complex of cyclin E with a kinase-negative mutant of CDK2 also exhibited these inhibitory effects, suggesting that cyclin E.CDK2 competes with KPC1 for access to the CDK inhibitory domain of p27. These results suggest that free p27 is recognized by the NH(2)-terminal region of KPC1, which also associates with KPC2, and that p27 is then polyubiquitylated by the COOH-terminal RING-finger domain of KPC1.
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PMID:Molecular dissection of the interaction between p27 and Kip1 ubiquitylation-promoting complex, the ubiquitin ligase that regulates proteolysis of p27 in G1 phase. 1574 3

The cyclin-dependent kinase (CDK) inhibitor p27(Kip1) (p27) is an important regulator of cell cycle progression controlling the transition from G to S-phase. Low p27 levels or accelerated p27 degradation correlate with excessive cell proliferation and poor prognosis in several forms of cancer. Phosphorylation of p27 at Thr187 by cyclin E-CDK2 is required to initiate the ubiquitination-proteasomal degradation of p27. Protecting p27 from ubiquitin-mediated proteasomal degradation may increase its potential in cancer gene therapy. Here we constructed a non-phosphorylatable, proteolysis-resistant p27 mutant containing a Thr187-to-Ala substitution (T187A) which is not degraded by ubiquitin-mediated proteasome pathway, and compared its effects on cell growth, cell-cycle control, and apoptosis with those of wild-type p27. In muristerone A-inducible cell lines overexpressing wild-type or mutant p27, the p27 mutant was more resistant to proteolysis in vivo and more potent in inducing cell-cycle arrest and other growth-inhibitory effects such as apoptosis. Transduction of p27(T187A) in breast cancer cells with a doxycycline-regulated adenovirus led to greater inhibition of proliferation, more extensive apoptosis, with a markedly reduced protein levels of cyclin E and increased accumulation of cyclin D1, compared with wild-type p27. These findings support the potential effectiveness of a degradation-resistant form of p27 in breast cancer gene therapy.
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PMID:Inducible expression of a degradation-resistant form of p27Kip1 causes growth arrest and apoptosis in breast cancer cells. 1599 62

Angiogenesis is a hallmark of melanoma progression. Antiangiogenic agents have been infrequently tested in patients with advanced melanoma. Experience with most other cancers suggests that single-agent application of angiogenic inhibitors is unlikely to have substantial clinical antitumor activity in melanoma. It is more likely that combinations of antiangiogenic agents with either chemotherapy or other targeted therapy will be needed to produce significant clinical benefit. In melanoma, numerous cellular pathways important to cell proliferation, apoptosis, or metastases have recently been shown to be activated. Activation occurs through specific mutations (B-RAF, N-RAS, and PTEN) or changes in expression levels of various proteins (PTEN, BCL-2, NF-kappaB, CDK2, and cyclin D1). Agents that block these pathways are rapidly entering the clinical setting, including RAF inhibitors (sorafenib), mitogen-activated protein kinase inhibitors (PD0325901), mammalian target of rapamycin inhibitors (CCI-779), and farnesyl transferase inhibitors (R115777) that inhibit N-RAS and proteasome inhibitors (PS-341) that block activation of nuclear factor-kappaB (NF-kappaB). It will be a challenge to evaluate these agents alone, in combination with each other, or with chemotherapy in patients with melanoma. Trials with large populations of biologically ill-defined tumors run the risk of missing clinical antitumor activity that is important for a particular yet-to-be-defined subset of patients. To rationally and optimally develop these targeted agents, it will be critical to adequately test for the presence of the presumed cellular target in tumor specimens and the effect of therapy on the proposed target (biological response). Investigators in this field will need to carefully plan these trials so that at the end of the day, we learn from both the failures and successes of targeted therapy.
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PMID:Molecular targets in melanoma from angiogenesis to apoptosis. 1660 62

Orderly progression through the cell cycle requires the transcriptional activation of histone genes to support packaging of newly replicated DNA. Induction of human histone gene expression is mediated by a co-activation complex containing transcription factor HiNF-P and its cofactor p220NPAT. Here, using cells synchronized in S-phase and in mitosis, as well as serum-stimulated cells, we have investigated how HiNF-P is regulated during the cell cycle and examined its stability relative to p220NPAT. We find that while HiNF-P is maintained at steady-state levels throughout the cell cycle, both HiNF-P and p220NPAT are actively degraded by the proteasome pathway. Importantly, elevation of HiNF-P levels enhances the stability of its co-activator p220NPAT. The HiNF-P-dependent stabilization of p220NPAT may reinforce signaling through the cyclin E/CDK2/p220NPAT pathway and contribute to coordinate control of histone gene expression.
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PMID:The histone gene transcription factor HiNF-P stabilizes its cell cycle regulatory co-activator p220NPAT. 1717 14

Forkhead box O (FoxO) transcription factors FoxO1, FoxO3a, FoxO4 and FoxO6, the mammalian orthologs of Caenorhabditis elegans DAF-16, are emerging as an important family of proteins that modulate the expression of genes involved in apoptosis, the cell cycle, DNA damage repair, oxidative stress, cell differentiation, glucose metabolism and other cellular functions. FoxO proteins are regulated by multiple mechanisms. They undergo inhibitory phosphorylation by protein kinases such as Akt, SGK, IKK and CDK2 in response to external and internal stimuli. By contrast, they are activated by upstream regulators such as JNK and MST1 under stress conditions. Their activities are counterbalanced by the acetylases CBP and p300 and the deacetylase SIRT1. Also, whereas polyubiquitylation of FoxO1 and FoxO3a leads to their degradation by the proteasome, monoubiquitylation of FoxO4 facilitates its nuclear localization and augments its transcriptional activity. Thus, the potent functions of FoxO proteins are tightly controlled by complex signaling pathways under physiological conditions; dysregulation of these proteins may ultimately lead to disease such as cancer.
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PMID:Dynamic FoxO transcription factors. 1764 72

The cyclin kinase inhibitor, p21, inhibits or arrests cell cycle progression in response to DNA damage and regulates the progression of apoptosis, either negatively or positively depending on the situation. The stability of p21 is regulated by its phosphorylation or through binding with partner molecules, and, when cells grow without DNA damage, the level of p21 is regulated by proteasome degradation. In this study, we analyzed the mechanism by which the basal expression level of p21 is stabilized. The transient expression of various p21 deletion mutants revealed a specific mutant with a deletion of 15-48 aa (Delta15-48C) that was extremely unstable. This mutant was stabilized by the proteasome inhibitor, lactacystin. Since the cysteine in the region of the alanine mutant did not destabilize p21, possible disulfide bonds formed by cysteines in the region are not responsible for the stabilization. The Delta15-48C was unstable in the cells stably expressing the 1-60 aa region, indicating that the 1-60 aa region did not function in trans. Fusion of the 1-60 aa fragment to the N-terminal of Delta15-48C stabilized the product, indicating that the 1-60 aa region in the molecule is effective for the stabilization. We constructed cells that stably expressed Delta15-48C. The Delta15-48C was unstable, but was stabilized by lactacystin. Irradiation (5 Gy) enhanced the expression of Delta15-48C without elevation of mRNA levels and increased the binding with cyclin A or CDK2. Taken together, the 15-48 aa region of p21 is essential for basal expression by preventing degradation by the proteasome, which is distinct from the mechanism induced by DNA damage.
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PMID:The N-terminal 15-48 region of cyclin kinase inhibitor p21 is a determinant of basal expression. 1780 69

Oncostatin M (OSM), an IL-6 family cytokine, either inhibits or enhances the growth of cells depending on cell type. Here, we report that OSM inhibits proliferation of skeletal muscle cells by blocking cell cycle progression from G(1) to S phase. OSM treatment significantly reduced levels of cyclin D1 protein and phosphorylation of retinoblastoma protein (Rb) at Ser-795, a CDK4-specific phosphorylation site. The OSM-induced cyclin D1 reduction correlated with decreased amount of the cyclin D1/p27 Kip1 complex and increased amounts of the CDK2/p27 Kip1 complex, resulting in inhibition of CDK2 activity. Results obtained with lactacystin, a proteasome inhibitor, demonstrated that cyclin D1 reduction occurred through ubiquitin/proteasome proteolysis. In addition, activation of STAT3, but not STAT1, is likely to regulate OSM-induced cyclin D1 reduction. Dominant negative (DN)-STAT3 blocked OSM-induced cyclin D1 reduction, and constitutively active-STAT3 also induced cyclin D1 reduction. These results suggest that OSM arrests skeletal muscle cell growth at the G1/S checkpoint and that this response occurs by an ubiquitin/proteasome-dependent cyclin D1 protein reduction which is regulated by STAT3.
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PMID:Oncostatin M induces growth arrest of skeletal muscle cells in G1 phase by regulating cyclin D1 protein level. 1797 56

Regular consumption of mesalazine has been associated with a reduced risk of colorectal cancer (CRC) in patients with inflammatory bowel disease. The molecular mechanisms underlying the antineoplastic effect of 5-aminosalicylic acid remain, however, poorly characterized. In this study, we examined whether mesalazine affects cell cycle progression and analyzed specific checkpoint pathways in experimental models of CRC. Mesalazine inhibited the growth of HCT-116 and HT-29 cells, two CRC cell lines that express either a wild-type or mutated p53. Cell cycle analysis revealed that mesalazine induced cells to accumulate in S phase. This effect was associated with a sustained phosphorylation of the cyclin-dependent kinase (CDK)2 at threonine 14 and tyrosine 15 residues, an event that inactivates the CDK2-cyclin complex and blocks S-G(2) phase cell cycle transition. Consistently, mesalazine reduced the protein content of CDC25A, a phosphatase that regulates CDK2 phosphorylation status. Analysis of upstream kinases that negatively control CDC25A expression showed that mesalazine enhanced the activation of CHK1 and CHK2. However, silencing of CHK1 and CHK2 did not prevent the mesalazine-induced CDC25A protein downregulation. In contrast, CDC25A protein ubiquitination and degradation and accumulation of cells in S phase following mesalazine exposure were reverted by proteasome inhibitors. Notably, mesalazine also inhibited CDC25A in human CRC explants. Finally, we showed that mesalazine downregulated CDC25A in CT26, a murine CRC cell line, and prevented the formation of CT26-derived tumors in mice. Data show that mesalazine negatively regulates CDC25A protein expression, thus delaying CRC cell progression.
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PMID:Mesalazine negatively regulates CDC25A protein expression and promotes accumulation of colon cancer cells in S phase. 1849 57

We previously found that the pro-apoptotic DNA damaging agent, cisplatin, mediated the proteasome-dependent degradation of Delta Np63 alpha associated with its increased phosphorylated status. Since Delta Np63 alpha usually plays an opposite role to p53 and TAp63 in human cancers, we tested the notion that phosphorylation events induced by DNA damage would affect the protein degradation of Delta Np63 alpha in HNSCC cells upon cisplatin exposure. We found that Delta Np63 alpha is phosphorylated in the time-dependent fashion at the following positions: S385, T397 and S466, which were surrounded by recognition motifs for ATM, CDK2 and p70s6K kinases, respectively. We showed that chemical agents or siRNA inhibiting the activity of ATM, CDK2 and p70s6K kinases blocked degradation of Delta Np63 alpha in HNSCC cells after cisplatin exposure. Site-specific mutagenesis of Delta Np63 alpha residues targeted for phosphorylation by ATM, CDK2 or p70s6k led to dramatic modulation of Delta Np63 alpha degradation. Finally, we demonstrated that the Delta Np63 alpha protein is a target for direct in vitro phosphorylation by ATM, CDK2 or p70s6K. Our results implicate specific kinases, and target phosphorylation sites in the degradation of Delta Np63 alpha following DNA damage.
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PMID:ATM kinase is a master switch for the Delta Np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon DNA damage. 1876 44

High-risk mucosal HPV E6 oncoproteins target a number of PDZ domain-containing substrates for proteasome mediated degradation. One of these, Discs Large (Dlg), is involved in the regulation of cell polarity and proliferation control. Previous studies had suggested that Dlg when hyperphosphorylated by osmotic shock, or when present in the nucleus could be preferentially targeted by E6. In this study we use phospho-specific antibodies directed against Dlg phosphorylated at residues S158 and S442 to show that these two observations are, in fact, linked. Dlg, when phosphorylated on S158 and S442 by CDK1 or CDK2, shows a preferential nuclear accumulation. However, these forms of Dlg are absent in cells derived from HPV-induced cervical cancers. Upon either proteasome inhibition or siRNA ablation of E6 expression, we see specific rescue of these phosphorylated forms of Dlg. These results demonstrate that nuclear forms of Dlg phosphorylated on its CDK phospho-acceptor sites has enhanced susceptibility to E6-induced degradation and place previous studies on the stress-induced phosphorylation of Dlg into a relevant biological context.
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PMID:The high-risk HPV E6 oncoprotein preferentially targets phosphorylated nuclear forms of hDlg. 1930 9


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