Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p53 tumor suppressor is regulated by the MDM2 oncoprotein through a negative feedback mechanism. MDM2 promotes the ubiquitination and proteasome-dependent degradation of p53, possibly by acting as a ubiquitin ligase. In cervical cancer cells containing high-risk human papillomaviruses (HPV), p53 is also targeted for degradation by the HPV E6 oncoprotein in combination with the cellular E6-AP ubiquitin ligase. In this report, we describe the identification of efficient antisense oligonucleotides against human E6-AP. The roles of MDM2 and E6-AP in p53 regulation were investigated using a novel E6-AP antisense oligonucleotide and a previously characterized MDM2 antisense oligonucleotide. In HPV16-positive and HPV-18 positive cervical cancer cells, inhibition of E6-AP, but not MDM2, expression results in significant induction of p53. In HPV-negative tumor cells, p53 is activated by inhibition of MDM2 but not E6-AP. Furthermore, treatment with both E6-AP and MDM2 antisense oligonucleotides in HPV-positive cells does not lead to further induction of p53 over inhibition of E6-AP alone. Therefore, E6-AP-mediated degradation is dominant over MDM2 in cervical cancer cells but does not have a significant role in HPV-negative cells.
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PMID:The roles of E6-AP and MDM2 in p53 regulation in human papillomavirus-positive cervical cancer cells. 1072 57

The Wnt signaling pathway functions reiteratively during animal development to control cell fate decisions. Inappropriate deregulation of this pathway leads to cancer in a number of tissues. The components that transduce the Wnt signal from the cell membrane to the cell nucleus are well conserved between vertebrates and Drosophila. A pivotal Wnt effector is the protein beta-catenin/Armadillo whose stability in the cytoplasm is low in unstimulated cells. Beta-catenin/Armadillo is targetted for proteasome-mediated degradation by a protein complex to which it binds. This complex consists of Axin, a putative scaffold protein which also binds to the tumor suppressor Adenomatous polyposis coli (APC) and glycogen synthase kinase 3 (GSK3)/Shaggy. Wnt signaling somehow inhibits the kinase activity of the quaternary complex. As a consequence, beta-catenin/Armadillo accumulates in the cytoplasm, translocates to the nucleus and becomes a transcriptional co-activator of T cell factor (TCF), the ultimate nuclear target of Wnt signaling. TCF is an architectural protein, mediating the assembly of multi-protein enhancer complexes. It cooperates with other enhancer-binding proteins and, together with beta-catenin/Armadillo, stimulates the transcription of Wnt target genes. Recently, repressors have been identified that prevent TCF from being active in the absence of Wnt signaling.
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PMID:The control of beta-catenin and TCF during embryonic development and cancer. 1072 86

The p53 tumor suppressor is activated by many diverse stress signals through mechanisms that result in stabilization and accumulation of the p53 protein. p53 is normally degraded through the proteasome following interaction with MDM2, which both functions as a ubiquitin ligase for p53 and shuttles to the cytoplasm, where p53 degradation occurs. Stabilization of p53 in response to stress is associated with inhibition of MDM2-mediated degradation, which has been associated with phosphorylation of p53 in response to DNA damage or activation of ARF. In this study we show distinct responses, as measured by phosphorylation, transcriptional activity, and subcellular localization, of p53 stabilized by different activating signals. Although normal cells and wild-type p53-expressing tumor cells showed similar responses to actinomycin D and camptothecin treatment, the transcriptional activity of stabilized p53 induced by deferoxamine mesylate, which mimics hypoxia, in normal cells was lost in all three tumor cell lines tested. Our results show that multiple pathways exist to stabilize p53 in response to different forms of stress, and they may involve down-regulation of MDM2 expression or regulation of the subcellular localization of p53 or MDM2. Loss of any one of these pathways may predispose cells to malignant transformation, although reactivation of p53 might be achieved through alternative pathways that remain functional in these tumor cells.
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PMID:Stress signals utilize multiple pathways to stabilize p53. 1075 6

The stability of p21(WAF1) and p53 is increased by UV radiation or proteasome inhibitors in normal and some tumor cells. However, p21(WAF1) can either stimulate in vitro assembly of active cyclin-kinase complexes at low concentrations or inhibit this activity at high concentrations. Also, ectopic p21(WAF1) over-expression has been reported to promote or suppress apoptosis, depending on the target cells. We have investigated changes in p21(WAF1) expression as a result of exposure to either 25 J/m(2) UV or 10 microM MG-115 proteasome inhibitor, both of which cause apoptosis in human C8161 melanoma cells. p21(WAF1) mRNA increased in response to UV irradiation but failed to accumulate at the protein level because of its early UV-activated degradation counteracted by proteasome inhibition. UV-mediated loss of p21(WAF1) protein preceding induction of p53 and cell death was greater in non-metastatic than in metastatic C8161 melanoma cells. No loss in p21(WAF1) occurred with apoptosis induced by 10 microM proteasome inhibitors MG-115 or lactacystin, mediated by over-expression of p21(WAF1). Our results suggest that conditions causing prolonged or permanent changes in basal levels of p21(WAF1) may impair its reversible cell-cycle checkpoint function, leading to irreversible growth arrest or cell death.
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PMID:Apoptosis-inducing levels of UV radiation and proteasome inhibitors produce opposite effects on p21(WAF1) in human melanoma cells. 1079 56

Physiological cell conditions, such as glucose deprivation and hypoxia, play a role in developing drug resistance in solid tumors. These tumor-specific conditions cause decreased expression of DNA topoisomerase IIalpha (topo IIalpha), rendering cells resistant to topo II-targeted drugs, such as etoposide and doxorubicin. We show here that inhibition of proteasome attenuated drug resistance by inhibiting topo IIalpha depletion induced by glucose starvation and hypoxia. topo IIalpha restoration was seen only at the protein levels, indicating that the topo IIalpha protein depletion occurred through a proteasome-mediated degradation mechanism. The stress-induced etoposide resistance was effectively prevented in vitro by the proteasome inhibitor lactacystin in both intrinsically resistant and sensitive tumor cells (colon cancer HT-29 and ovarian cancer A2780 cells, respectively). Furthermore, lactacystin effectively enhanced the antitumor activity of etoposide in the refractory HT-29 xenograft. These results indicate that lactacystin could serve as a new therapeutic agent to circumvent resistance to topo II-targeted chemotherapy in solid tumors.
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PMID:Proteasome inhibition circumvents solid tumor resistance to topoisomerase II-directed drugs. 1081 Nov 20

The ubiquitin proteasome pathway is a highly conserved intracellular pathway for the degradation of proteins. Many of the short-lived regulatory proteins which govern cell division, growth, activation, signaling and transcription are substrates that are temporally degraded by the proteasome. In recent years, new and selective inhibitors of the proteasome have been employed in cell culture systems to examine the anti-tumor potential of these agents. This review covers the chemistry of selected proteasome inhibitors, possible mechanisms of action in cell culture and the in vivo examination of proteasome inhibitors in murine and human xenograft tumor models in mice. One inhibitor, PS-341, has recently entered Phase I clinical trials in cancer patients with advanced disease to further test the potential of this approach.
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PMID:Proteasome inhibition: a new strategy in cancer treatment. 1085 91

In this study, a computer-assisted reverse immunology approach was utilized in order to identify potentially antigenic peptides derived from the differentiation antigen TRP-2, a melanosomal protein frequently expressed in melanoma. Among the seven peptides complying with HLA-A2.1-binding motifs, two induced specific CD8(+) cytotoxic T lymphocytes. HLA-A2.1(+) melanoma cells expressing TRP-2 were lysed by clones specific for TRP-2(360-368) (TLDSQVMSL) peptide, thus identifying it as a naturally processed epitope. Other T-cell clones directed against TRP-2(476-484) (VMGTLVALV) were unable to lyse HLA-matched TRP-2(+) cell lines. The role of intracellular proteolytic processing in the generation of this epitope was investigated by transfecting mini-genes encoding the TRP-2(476-484) peptide alone or carrying N- or C-terminal extensions. Specific T-cell clones recognized target cells expressing the cytotoxic T-lymphocyte (CTL)-defined epitope or its C-terminally extended precursor, but failed to recognize cells expressing the N-terminally extended TRP-2(476-484) peptide, suggesting the presence of a negative processing signal (NPS). Regarding C-terminus-flanking regions, mutational analysis indicates that the GLY485 residue plays a key role in the processing of the TRP-2(476-484) epitope. Interestingly, proteasome inhibitors preventing the generation of the MART-1/Melan-A(27-35) immunodominant melanoma tumor-associated antigen (TAA) promoted detectable presentation of TRP-2(476-484) epitope in HLA-A2.1(+) and TRP-2(+) tumor lines, as witnessed by cytokine release by specific T-cell clones.
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PMID:Naturally processed and concealed HLA-A2.1-restricted epitopes from tumor-associated antigen tyrosinase-related protein-2. 1086 82

Expression of NY-ESO-1 in a high proportion of different human tumors makes this protein a very attractive vaccine target. NY-ESO-1 peptides, recognized by HLA-A2-restricted CTL, have recently been described. However, it remains unclear how efficiently tumors generate these epitopes, and whether peptide analogues can be used for optimal expansion and activation of NY-ESO-1-specific HLA-A2-restricted CTL. By generating unique CTL clones, we demonstrate that NY-ESO-1-positive tumor cells are efficiently killed by HLA-A2-restricted CTL specific for the peptide epitope NY-ESO-1 157-165. Presentation of this epitope is not affected by the presence or absence of the proteasome subunits low molecular proteins 2 and 7 and is not blocked by proteasome inhibitors, while it is impaired in the TAP-deficient cell line LBL 721.174. NY-ESO-1 157-165 peptide analogues were compared for their antigenicity and immunogenicity using PBL from melanoma patients. Three peptides, containing the carboxyl-terminal cysteine substituted for either valine, isoleucine, or leucine, were recognized at least 100 times more efficiently than the wild-type peptide by specific CTL. Peptide analogues were capable of stimulating the expansion of NY-ESO-1-specific CTL from PBL of melanoma patients much more efficiently than wild-type peptide. These findings define the processing requirements for the generation of the NY-ESO-1 157-165 epitope. Identification of highly antigenic NY-ESO-1 peptide analogues may be important for the development of vaccines capable of expanding NY-ESO-1-specific CTL in cancer patients.
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PMID:Identification of NY-ESO-1 peptide analogues capable of improved stimulation of tumor-reactive CTL. 1087 70

Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene causes the familial cancer syndrome, VHL disease, characterized by a predisposition to renal cell carcinoma and other tumor types. Loss of VHL gene function also is found in a majority of sporadic renal carcinomas. A preponderance of the tumor-disposing inherited missense mutations detected in VHL disease are within the elongin-binding domain of VHL. This region mediates the formation of a multiprotein VHL complex containing elongin B, elongin C, cul-2, and Rbx1. This VHL complex is thought to function as an E3 ubiquitin ligase. Here, we report that VHL proteins harboring mutations which disrupt elongin binding are unstable and rapidly degraded by the proteasome. In contrast, wild-type VHL proteins are directly stabilized by associating with both elongins B and C. In addition, elongins B and C are stabilized through their interactions with each other and VHL. Thus, the entire VHL/elongin complex is resistant to proteasomal degradation. Because the elongin-binding domain of VHL is frequently mutated in cancers, these results suggest that loss of elongin binding causes tumorigenesis by compromising VHL protein stability and/or potential VHL ubiquitination functions.
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PMID:Elongin BC complex prevents degradation of von Hippel-Lindau tumor suppressor gene products. 1090 11

The ubiquitin-proteasome pathway is becoming an attractive target in cancer therapy. The inhibitors of proteasomes have recently been shown to induce apoptosis of tumor cells in vitro and to exert significant antitumor effects in murine tumor models in vivo. Proteasome inhibitors, also prevent NF-kappa B activation. Since this transcription factor is responsible for counteracting apoptosis induced by numerous agents, and proteasome inhibitors have already proved efficacious in increasing the proapoptotic activity of TNF in vitro, we decided to evaluate the antitumor effects of the combined PSI and TNF treatment against a murine C-26 carcinoma. Both agents separately exerted moderate antitumor efficacy. However, their combination proved to exert dramatic antitumor activity with retardation of tumor growth and prolongation of mice survival time. Moreover, 50% of the mice were completely cured by this drug combination. Unexpectedly, there was no potentiation of the cytostatic/cytotoxic effects of these drugs in in vitro assays which argues against the direct influence on C-26 cells. Similarly, the influence of these drugs on tumor induced angiogenesis does not seem to explain the observed antitumor effects. Further studies are necessary to explain the striking antitumor effects of the PSI and TNF combination.
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PMID:Synergistic antitumor effects of a selective proteasome inhibitor and TNF in mice. 1092 98


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