Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunochemical methods were used to examine the effect of viral infection on the dynamics of intracellular ubiquitin pools. Infection of either the human lung carcinoma line A-549 or the mouse fibroblast line L929 with encephalomyocarditis virus had little effect on either the distribution or fractional level of intracellular ubiquitin conjugates. In contrast, viral infection resulted in a significant decline in the steady state content of the mono-ubiquitin conjugate to histone 2A (uH2A). Prior treatment with interferons protected against this decrease of uH2A. Furthermore, interferons induced the de novo synthesis of a 15-kDa protein immunologically related to ubiquitin. The ubiquitin cross-reactive protein (UCRP) was not constitutively present in control cells but was significantly induced in various cells sensitive to the biological effects of interferons. Induction of UCRP with respect to both time and interferon concentration dependence closely paralleled the appearance of resistance to viral infection and could be blocked by low levels of actinomycin D. Subsequent studies demonstrated that UCRP was identical to an interferon-induced 15-kDa protein whose sequence has recently been reported (Blomstrom, D. C., Fahey, D., Kutny, R., Korant, B. D., and Knight, E. (1986) J. Biol. Chem. 261, 8811-8816). An authentic sample of the 15-kDa protein was found to co-migrate with UCRP and to cross-react with two different anti-ubiquitin antibodies. Using the authentic 15-kDa protein as a standard, UCRP accumulated to 6.2 +/- 0.5 pmol/10(6) cells and 34 +/- 2 pmol/10(6) cells in interferon-treated A-549 and L929 cultures, respectively. Comparison of the primary sequence of the 15-kDa protein to that of ubiquitin indicated that the former is composed of two domains, each of which bears striking homology to ubiquitin. These observations suggest that the 15-kDa protein may represent one example of a functionally distinct family of ubiquitin-like proteins.
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PMID:Interferon induces a 15-kilodalton protein exhibiting marked homology to ubiquitin. 244 Aug 90

Ubiquitin cross-reactive protein (UCRP), a 15-kDa interferon-induced protein, is a sequence homolog of ubiquitin that is covalently ligated to intracellular proteins in a parallel enzymatic reaction and is found at low levels within cultured cell lines and human tissues not exposed to interferon. Ubiquitin and UCRP ligation reactions apparently target distinct subsets of intracellular proteins, as judged from differences in the distributions of the respective adducts revealed on immunoblots. In this study, successive passages of the human lung carcinoma line A549 in the presence of neutralizing antibodies against alpha and beta interferons had no effect on the levels of either free or conjugated UCRP, indicating that these UCRP pools are constitutively present within uninduced cells and are thus not a consequence of autoinduction by low levels of secreted alpha/beta interferon. In an effort to identify potential targets for UCRP conjugation, the immunocytochemical distribution of UCRP was examined by using affinity-purified polyclonal antibodies against recombinant polypeptide. UCRP distributes in a punctate cytoskeletal pattern that is resistant to extraction by nonionic detergents (e.g., Triton X-100) in both uninduced and interferon-treated A549 cells. The cytoskeletal pattern colocalizes with the intermediate filament network of epithelial and mesothelial cell lines. Immunoblots of parallel Triton X-100-insoluble cell extracts suggest that the cytoskeletal association largely results from the noncovalent association of UCRP conjugates with the intermediate filaments rather than direct ligation of the polypeptide to structural components of the filaments. A significant increase in the sequestration of UCRP adducts on intermediate filaments accompanies interferon induction. These results suggest that UCRP may serve as a trans-acting binding factor directing the association of ligated target proteins to intermediate filaments.
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PMID:Conjugates of ubiquitin cross-reactive protein distribute in a cytoskeletal pattern. 752 57

Cyclin D1, which is suggested to have a role in G1 control during the cell cycle, is genetically linked to BCL-1 and is widely overexpressed in parathyroid, breast, and squamous cancer cells. We postulated that cyclin D1 regulation may also be important in lung cancer. Therefore, we characterized the cell cycle-dependent expression of cyclin D1 at both mRNA and protein levels in synchronized human A549 lung carcinoma cells. Monospecific anti-cyclin D1 C-terminal peptide antibodies recognized both p36cyclinD1 and an as-yet uncharacterized 45 kD protein (p45). A549 cells were synchronized with well-studied drugs. Cyclin D1 mRNA expression remained relatively constant, with less than a twofold fluctuation during the cell cycle and with a minor peak at M phase. However, the p36cyclinD1 protein fluctuated during the A549 cell cycle and was expressed at very low levels in late G1 and at the G1/S boundary, but then increased in S phase and peaked at M phase. In contrast, p45 protein was expressed at relatively high levels in late G1 and reached maximal levels at the G1/S boundary, was expressed at decreased levels in S phase, and then had disappeared by M phase. Moreover, p45 was highly expressed only in transformed alveolar epithelial cells, but not in normal rat alveolar epithelial cells or fetal rat lung fibroblasts in primary cultures. In mink Mv1Lu cells, the expression of p45 was totally blocked by transforming growth factor-beta 1 treatment or contact inhibition. p45 protein was phosphorylated on serine, threonine, and tyrosine residues in A549 cells in culture. The phosphorylation of the p45 protein was cell cycle-regulated and reached its maximal levels at G2/M phase. The p45 protein had a different peptide map from p36cyclinD1 after cleavage with N-chlorosuccinimide. Immunoprecipitation studies showed that p45 was also anti-ubiquitin immunoreactive during the cell cycle. We conclude that p36cyclinD1 and the p45 protein are differentially regulated in a cell cycle-dependent manner in A549 cells. Although p45 is antigenically related to p36cyclinD1, it is probably not a closely cyclin-related protein. We speculate that p45 may be associated with malignant transformation and may play a distinct role from p36cyclinD1 in regulation of the cell cycle in A549 cells.
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PMID:Cell cycle-dependent expression of cyclin D1 and a 45 kD protein in human A549 lung carcinoma cells. 813 59

The biological effect of type 1 interferons is proposed to arise in part from the conjugation of ubiquitin cross-reactive protein (UCRP), the ISG15 gene product, to intracellular target proteins in a process analogous to that of its sequence homolog ubiquitin, a highly conserved 8.6-kDa polypeptide whose ligation marks proteins for degradation via the 26 S proteasome. Inclusion of CoCl2 during the purification of recombinant UCRP blocks the proteolytic inactivation of the polypeptide occurring by cleavage of the carboxyl-terminal glycine dipeptide required for activation and subsequent ligation. Intact UCRP supports a low rate of ubiquitin-activating enzyme (E1)-dependent ATP:PPi exchange but fails to form a stoichiometric E1-UCRP thiol ester or undergo transfer to ubiquitin carrier protein (E2). The binding affinity of E1 for UCRP is significantly diminished relative to that of ubiquitin. These results suggest that UCRP conjugation proceeds through an enzyme pathway distinct from that of ubiquitin, at least with respect to the step of activation. This was confirmed for an in vitro conjugation assay in which 125I-UCRP could be ligated in an ATP-dependent reaction to proteins present within an A549 human lung carcinoma cell extract and could be competitively inhibited by excess unlabeled UCRP but not ubiquitin. Other results demonstrate that 125I-UCRP conjugation is significantly increased in cell extracts after 24 h of incubation in the presence of interferon-beta, consistent with the late induction of UCRP conjugating activity. Thus, interferon-responsive cells contain a pathway for UCRP ligation that is parallel but distinct from that of ubiquitin.
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PMID:Conjugation of the 15-kDa interferon-induced ubiquitin homolog is distinct from that of ubiquitin. 855 May 81

This retrospective immunohistochemical study compares the expression of five stress-response (heat-shock) proteins (srp's) [srp 90, srp 72, srp 27, alpha B-crystallin and ubiquitin], p53 protein and proliferating cell nuclear antigen (PCNA) in 118 primary brain tumors and 21 carcinoma metastases to the central nervous system. Serial sections of formalin-fixed, paraffin-embedded tissues were used. Most astrocytomas (9/13), ependymomas (5/5), glioblastoma multiforme (GBM) (11/12), schwannomas (19/21), meningiomas (22/23) and breast carcinoma metastases (Br-Mt) (9/10), and some medulloblastomas (5/15), primitive neuroectodermal tumors (PNETs) (5/11), pituitary adenomas (4/7) and lung carcinoma metastases (6/11), but none of 10 oligodendrogliomas had tumor cells that expressed one or more (up to five) srp's. The percentage of tumors with p53-positive cells was variable; the proportion was highest among srp-expressing GBMs (mean: 16.1%) and Br-Mts (mean: 15.3%). The mean PCNA-labeling index (LI) also varied, ranging from 1.2% in the group of pituitary adenomas to 24.5% in Br-Mts, with GBMs (20.4%) and medulloblastomas (18.4%) approaching the latter value. PCNA-LI was higher in the astrocytomas, GBMs, medulloblastomas and PNETs that expressed srp's than in those did not. A high proportion of p53-positive cells (31.3 to 59.0%) and the highest PCNA-LIs (41.0 to 49.0%) were seen in two GBMs and one Br-Mt that expressed all five srp's. We conclude that primary and metastatic tumors of the brain produce one or more stress-related proteins, and that a variable proportion of the tumor cells have immunohistochemically-detectable p53, the expression of which may depend, at least in part, on the growth potential of a given tumor.
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PMID:Brain tumor: immunohistochemical studies on the stress-response proteins, p53 protein and proliferating cell nuclear antigen. 886 93

The human Unp gene at 3p21.3 has sequence similarity to ubiquitin proteases and has been suggested to play a role in carcinogenesis of the lung (Gray et al., 1995). To investigate this possibility, we isolated cDNAs from several human tissue libraries and found evidence for two major isoforms, encoding proteins predicted to either contain an internal 47 amino acid segment or not. Both are functional in deubiquitination assays, and mutation of a critical conserved cysteine residue to alanine abolished activity. Unp specifies two closely-migrating transcripts whose relative abundance varies among human adult tissues. Antibodies specific to UNP confirm the presence of at least two endogenous protein isoforms of approximately 105-110 kDa in cell lysates, as predicted from the cDNA sequences. Cellular fractionation and immunocytochemistry revealed UNP expression localized primarily in the cytoplasm. When we examined a panel of lung-derived cell lines for both UNP mRNA and protein expression, we found reduced levels of UNP protein in all four small cell lung carcinoma cell lines tested. These findings directly contradict and offer alternative interpretations to a number of previously published observations on Unp.
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PMID:The human UNP locus at 3p21.31 encodes two tissue-selective, cytoplasmic isoforms with deubiquitinating activity that have reduced expression in small cell lung carcinoma cell lines. 946 33

The implantation of the Lewis lung carcinoma (a fast-growing mouse tumour that induces cachexia) to both wild-type and transgenic mice for the soluble TNF receptor type I protein (sTNF-R1) resulted in a considerable loss of carcass weight in both groups. However, while in the wild-type mice there was a loss of both fat and muscle, in the transgenic mice muscle waste was not affected to the same extent as in the wild-type group. Muscle waste in wild-type mice was accompanied by an increase in the fractional rate of protein degradation, while no changes were observed in protein synthesis. The result was a decreased rate of protein accumulation which accounted for the muscle weight loss observed as a result of the tumour burden. In contrast, transgenic mice did not have such low rates of protein accumulation after tumour implantation. The increase in protein degradation in the tumour-bearing transgenic mice was accompanied by a similar increase in protein synthesis which compensated for the loss of muscle protein by degradation. Both tumour-bearing groups showed an enhanced expression of ubiquitin and proteasome C8 subunit genes, all of them related to the activation of the ATP-dependent proteolytic system in skeletal muscle. It is suggested that TNF may, in part, be responsible for the loss of protein in skeletal muscle of tumour-bearing mice.
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PMID:Protein turnover in skeletal muscle of tumour-bearing transgenic mice overexpressing the soluble TNF receptor-1. 975 Dec 52

The implantation of the Lewis lung carcinoma (a fast-growing mouse tumour that induces cachexia) to both wild-type and gene-deficient mice for the TNF-alpha receptor type I protein (Tnfr1 degree/Tnfr1 degree), resulted in a considerable loss of carcass weight in both groups. However, while in the wild-type mice there was a loss of both fat and muscle, in the gene-knockout mice muscle wastage was not affected to the same extent. In both groups, tumour burden resulted in significant increases in circulating TNF-alpha, a cytokine which, as we have previously demonstrated, can induce protein breakdown in skeletal muscle. Muscle wastage in wild-type mice was accompanied by an increase in the fractional rate of protein degradation, while no changes were observed in protein synthesis. The result is a decreased rate of protein accumulation that accounts for the muscle weight loss observed as a result of tumour burden. In contrast, gene knockout mice did not have significantly lower rates of protein accumulation as a result of tumour implantation. The increase in protein degradation in the tumour-bearing wild mice was accompanied by an enhanced expression of both ubiquitin and proteasome subunit genes, all of them related to the activation of the ATP-dependent proteolytic system in skeletal muscle. Tumour-bearing gene-deficient mice did not show any increase in gene expression. It is concluded that TNF-alpha (alone or in combination with other cytokines) is responsible for the activation of protein breakdown in skeletal muscle of tumour-bearing mice.
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PMID:Role of TNF receptor 1 in protein turnover during cancer cachexia using gene knockout mice. 978 14

IFNs are a family of cytokines involved in antiviral defense, cell growth regulation and immune activation. IFNs either inhibit cell proliferation or control apoptosis depending on factors such as cell type and state of cell differentiation. It is important to determine how IFN-induced gene products interact with other cellular proteins to produce these responses. We have investigated the effect of IFNalpha 2b on a human small cell lung carcinoma (SCLC) cell line H82. We have found that IFNalpha efficiently induces apoptosis in H82 cells. The induction of apoptosis by IFNalpha 2b is accompanied by decreased levels of c-myc and Cdk2. We have also observed that in H82 cells IFNalpha induces downregulation of p27 and this is in contrast to the upregulation of p27 observed in other cell types where IFNs induce cell cycle arrest. IFNalpha-induced downregulation of p27 is due to protein destabilization and can be prevented by the proteasome inhibitor LLnL. The data suggest that in H82 cells, IFNalpha 2b induces degradation of p27Kip1 independently of CDK2 kinase activity and through a ubiquitin or ubiquitin-related pathway and that the degradation of p27Kip1 could be a molecular event of importance for IFN-induced apoptosis in cancer cells.
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PMID:IFNalpha 2b induces apoptosis and proteasome-mediated degradation of p27Kip1 in a human lung cancer cell line. 1118 68

Strong expression of high-molecular-weight (HMW) heat-shock proteins (HSP) by lung carcinoma has been documented using immunohistochemistry. Far less is known about the expression of low-molecular-weight (LMW) HSP in lung cancer. We compared the quantitative expression of HMW (HSP-60, HSP-70) and LMW (HSP-27, ubiquitin) HSP in tumor and non-tumor lung tissue obtained from 47 patients undergoing surgical resection of lung carcinoma. HSP levels were determined in cell lysates from tissue samples by ELISA using streptavidin-biotin technology. Results were normalized to total protein content measured by spectrophotometry. Compared to disease-free lung tissue, tumor tissue samples showed higher levels of both HSP-60 (median value: 227 pg versus 96 pg per mg protein (P<0.001 by Wilcoxon Rank test for paired data) and HSP-70 (median value: 525 ng versus 401 ng per mg protein (P=0.01 by Wilcoxon Rank test for paired data). Tumor and tumor-free tissues show similar levels of ubiquitin and HSP-27. Neither the survival rate nor the histologic type and extent of cancer are correlated with the observed differences in HSP-60 and HSP-70 expression (P>0.1 by one way analysis of variance for repeated measures with one between subject factor). Our data confirm, on a quantitative basis, the increased expression of HSP-60 and HSP-70 in non-small-cell lung carcinoma. However, no prognostic value was found to be associated with this over-expression. In contrast, LMW stress proteins such as ubiquitin and HSP-27, although implicated in cellular processes potentially related to malignant transformation, show no increased expression in lung carcinoma.
Lung Cancer 2001 Jul
PMID:Increased expression of high but not low molecular weight heat shock proteins in resectable lung carcinoma. 1142 96


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