Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hamster tumor cell lines obtained with the Rous sarcoma virus and characterized by a high metastatic activity in vitro were transfected with the gene for C2+/calmodulin-dependent serine-threonine death-associated protein kinase (DAPk). Expression of DAPk in tumor cells dramatically reduced their survival in the blood of syngenic animals and their ability to produce metastases, but did not affect their tumorigenicity or the primary tumor growth. The DAPk-induced change in the metastatic phenotype was not accompanied by substantial changes in production and phosphorylation of v-Src or focal adhesion proteins (focal adhesion kinase and paxilline). The resulting system of transfected cells with a modulated metastatic potential provide a convenient model to study the molecular mechanisms of tumor progression at various steps.
Mol Biol (Mosk)
PMID:[Suppression of the metastatic potential of oncogene v-src-transformed cells as a result of activity of the exogenous DAP kinase]. 1206 33

An ideal therapeutic for cancer would be one that selectively targets to tumor cells, is nontoxic to normal cells, and that could be systemically delivered, thereby reaching metastases as well as primary tumor. Immunoliposomes directed by monoclonal antibody or its fragments are promising vehicles for tumor-targeted drug delivery. However, there is currently very limited data on gene delivery using these vehicles. We have recently described a cationic immunoliposome system directed by a lipid-tagged, single-chain antibody Fv fragment (scFv) against the human transferrin receptor (TfR) that shows promising efficacy for systemic p53 tumor suppressor gene therapy in a human breast cancer metastasis model. However, the extremely low yield of this lipid-tagged scFv limited further downstream development and studies. Here we report a different expression strategy for the anti-TfR scFv, which produces high levels of protein without any tags, and a different approach for complexing the targeting scFv to the liposomes. This approach entails covalently conjugating the scFv to the liposome via a cysteine at the 3'-end of the protein and a maleimide group on the liposome. Our results show that this conjugation does not impair the immunological activity or targeting ability of the scFv. The scFv-cys targets the cationic liposome-DNA complex (lipoplex) to tumor cells and enhances the transfection efficiencies both in vitro and in vivo in a variety of human tumor models. This scFv-immunoliposome can deliver the complexed gene systemically to tumors in vivo, where it is efficiently expressed. In comparison with the whole antibody or transferrin molecule itself, the scFv has a much smaller size for better penetration into solid tumors. It is also a recombinant protein rather than a blood product; thus, large scale production and strict quality control are feasible. This new approach provides a promising system for tumor-targeted gene delivery that may have potential for systemic gene therapy of various human cancers.
Mol Cancer Ther 2002 Mar
PMID:Systemic tumor-targeted gene delivery by anti-transferrin receptor scFv-immunoliposomes. 1248 50

The activation of the NF-kappaB family of transcription factors plays a crucial role in oncogenesis. The IkappaB family has the ability to retain the NF-kappaB in an inactive complex in the cytoplasm. Recently, mutations of the IkappaBalpha gene were found in Hodgkin's lymphoma, which allows NF-kappaB proteins to translocate into the nucleus in an active form. In this report, we describe a mutational analysis of IkappaBalpha for primary tumor cells obtained from patients with a variety of hematologic malignancies (acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, hairy cell leukemia, adult T-cell leukemia, and mantle cell lymphoma) as well as 15 leukemia, lymphoma, and myeloma cell lines (HL60, U937, HEL, K562, NALM1, Jurkat, JM, MOLT4, Raji, KS1, OKM2T, OKM3T, F6T, Su9T01, and C2-2). RT-PCR, followed by direct sequencing, was performed and all samples expressed IkappaBalpha. One missense mutation was identified in a primary effusion lymphoma cell line, KS1. However, NF-kappaB (p65) protein was absent from the nucleus of KS1 immunohistochemically, suggesting that the mutation did not alter the function of IkappaBalpha in this case. Taken together, although it is not clear whether normal IkappaBalpha protein was expressed in hematologic malignancies, mutations of IkappaBalpha could be rare events in these diseases, except for Hodgkin's lymphoma. Alterations of other members of NF-kappaB/ IkappaB family proteins might act on the development of hematologic malignancies.
Int J Mol Med 2003 Feb
PMID:Mutational analysis of IkappaBalpha in hematologic malignancies. 1252 85

12,13-Dihydro-5-[2-(dimethylamino)ethyl]-4H-benzo[c] pyrimido[5,6,1-jk] carbazole-4,6,10(5H,11H)-trione hydrochloride (ER-37328) is a novel topoisomerase II poison with potent tumoricidal activity against solid tumor cells both in vitro and in vivo. Here, we describe studies on the effects of ER-37328 on the primary tumor, liver metastasis, and survival in a murine Colon 38 orthotopic transplantation model. When ER-37328 (10 mg/kg) was administered i.v. at 11 days or 20 days after transplantation, strong regression of the primary tumor was observed on both administration schedules. On the later schedule, ER-37328 completely blocked liver metastasis, whereas the mean number of metastases in the control group was 23.9. To examine the antitumor activity against Colon 38 at the liver in more detail, ER-37328 was administered to mice that had received an inoculation of Colon 38 tumor into the liver. ER-37328 showed strong tumor-regression activity against Colon 38 growing in the liver. In addition, administration of ER-37328 on a schedule of every 7 days four times caused a significant increase of 79% in life span in the orthotopic transplantation model, calculated by using mean survival times. Pharmacokinetic study revealed that ER-37328 was highly distributed to the tumor and organs. The ratios of the area under the concentration-time curves of ER-37328 in the tumor, lung, liver, and kidney versus plasma were 81, 77, 47, and 40, respectively. This high distribution to the tumor and liver may explain the potent antitumor activity of ER-37328 against Colon 38 tumor in the liver. In conclusion, the topoisomerase II poison ER-37328 is a promising candidate for clinical application against colon cancer.
Mol Cancer Ther 2003 Jan
PMID:Effects of ER-37328 on primary tumor, liver metastasis, and life span in a murine colon 38 orthotopic transplantation model. 1253 73

While human prostate cancers and cell lines express Fas, most of these cell lines are resistant to Fas-mediated death. In the present studies we addressed the ability of IFN-gamma to influence Fas-mediated cell death in prostate cancer cells. In vitro exposure of the human cell lines LNCaP and PC3 and the mouse cell line RM-1 to agonist anti-Fas antibody and/or soluble Fas ligand resulted in killing of only PC3 cells. However, preincubation with IFN-gamma resulted in synergistic killing in all three cell lines. In vitro treatment of RM-1 with a replication-incompetent adenovirus expressing mouse FasL (Ad.FasL) resulted in maximal cell kill near 40%, which correlated with baseline Fas expression. The addition of IFN-gamma enhanced cell kill to a degree consistent with the resulting higher levels of Fas and maintained synergistic killing at very low doses of vector. Co-inoculation of orthotopic RM-1 primary tumors with Ad.mFasL and an adenovirus expressing mouse IL-12 (Ad.mIL-12) to drive host production of IFN-gamma negated the survival advantage of Ad.mIL-12 alone. However, the staggered injection of Ad.mIL-12 and Ad.FasL achieved almost threefold higher levels of apoptosis in primary tumor tissue and doubled median survival. Therefore, IFN-gamma is capable of bestowing increased sensitivity to Fas-mediated cell death in prostate cancer cells and, in a gene therapy approach, may define a powerful tool to treat prostate cancers.
Mol Ther 2003 Feb
PMID:IFN-gamma sensitization of prostate cancer cells to Fas-mediated death: a gene therapy approach. 1259 6

A 63-year-old man was admitted to our hospital for complaints of a painless knot in his right testicle. The patient underwent orchiectomy for suspicion of malignancy. Pathologic examination detected a firm, circumscribed mass that consisted histologically of noncohesive, large, undifferentiated tumor cells diffusely infiltrating the testicular interstice. Because of the patient's advanced age and the structure of the neoplastic cells, the differential diagnosis favored a lymphoma over a malignant germ cell tumor but also included a dedifferentiated metastatic neoplasm. Immunohistochemistry was tailored accordingly and was completed using three successive panels of antibodies. Immunostaining with the first panel of antibodies directed against leukocyte epitopes (CD45, CD20, and CD3) remained negative and made a lymphoma unlikely. The subsequent panel (cytokeratin AE1/3, cytokeratin 18, and HMB-45) helped to rule out a malignant melanoma and aided to settle the diagnosis of a metastatic carcinoma. The reaction pattern of the last panel of antibodies pointed to a pulmonary origin of the putative primary tumor (PSA-negative, TTF-1-positive, and CK20-negative). The diagnosis of a metastasized poorly differentiated adenocarcinoma of the lung was confirmed by autopsy 5 months later. This case represents the extremely rare occurrence of a testicular metastasis as a primary manifestation of an occult neoplasm and shows the usefulness of an integrated site-specific clinicomorphologic approach that should precede and guide the choice of diagnostic immunoreagents.
Appl Immunohistochem Mol Morphol 2003 Mar
PMID:Immunohistochemical assessment of a testicular tumor in a 63-year-old patient: proposal for an integrated clinicopathologic approach. 1261 Mar 64

A nonhydrolyzable ether analogue of RRR-alpha-tocopherol, 2,5,7,8-tetramethyl-2R-(4R, 8R, 12-trimethyltridecyl)chroman-6-yloxyacetic acid, called RRR-alpha-tocopheryloxyacetic acid or RRR-alpha-tocopherol ether-linked acetic acid analogue (alpha-TEA), exhibits antitumor activity in vitro and in vivo using a syngeneic BALB/c mouse mammary tumor model (line 66 clone 4 stably transfected with green fluorescent protein). Treatment of cells with 5, 10, and 20 micro g/ml alpha-TEA for 3 days produced 6, 34, and 50% apoptosis, respectively, and treatment of cells with 10 micro g/ml for 2, 3, 4, and 5 days produced 20, 35, 47, and 58% apoptosis, respectively. A liposomal formulation of alpha-TEA administered by aerosol reduced s.c. tumor growth and lung metastasis. Alpha-TEA-treated animals showed a significant decrease in tumor volumes over 17 days of aerosol treatment (P < 0.001). Forty percent of aerosol as well as untreated control mice had visible, macroscopic lung metastases versus none (0%) of the alpha-TEA-treated mice. On the basis of fluorescence microscopic examination of the surface (top and bottom) of flattened whole left lung lobes, an average of 60 +/- 15 and 102 +/- 17 versus 11 +/- 4 fluorescent microscopic metastases was observed in aerosol control and untreated control versus alpha-TEA-treated animals, respectively. Alpha-TEA formulated in ethanol + peanut oil (5 mg/mouse/day) delivered by gavage did not reduce s.c. primary tumor burden; however, fluorescent microscopic lung metastases were significantly reduced (P < 0.0021). In summary, alpha-TEA formulated in liposomes and delivered by aerosol is a potent antitumor agent and reduces lung metastasis.
Mol Cancer Ther 2003 May
PMID:Novel vitamin E analogue decreases syngeneic mouse mammary tumor burden and reduces lung metastasis. 1274 5

Although many reports suggest that aberrant regulation of cytokine signaling pathways via the interleukin-2 receptor (IL-2R) induces tumorigenic transformation, constitutively active IL-2R in tumors has not been reported. We searched for genomic alteration of the IL-2/15R beta-subunit gene (IL-2/15R beta) in cytokine-independent cell lines established from radiation-induced mouse thymic lymphomas. In the TL34 cell line and its primary tumor, one of the IL-2/15R beta alleles was rearranged by the insertion of an intracisternal A particle (IAP) retrotransposon. The IAP-IL2/15R beta chimeric gene expressed chimeric mRNA in which IAP-coding Gag-Pol mRNA was fused to IL-2/15R beta mRNA and coded for Gag-Pol-IL-2/15R beta chimeric protein. Forced expression of the Gag-Pol-IL-2/15R beta chimeric cDNA in a mouse cytotoxic T-cell line (CTLL-2) converted IL-2-dependent cell growth to IL-2-independent growth, suggesting that the chimeric protein activates some of the IL-2 signaling pathways necessary for cell proliferation. Downregulation of the expression of the Gag-Pol-IL-2/15R beta chimeric protein in TL34 by antisense RNA inhibited cell growth, and concomitantly reduced the level of c-myc protein. These results suggest that the Gag-Pol-IL-2/15R beta is a constitutively active form that transmits proliferative signals by expressing downstream target genes, including c-myc. Thus, we demonstrated that the chimeric receptor gene produced by the insertion of an IAP functions as an oncogene by providing IL-2-independent autonomous growth potential.
Mol Carcinog 2003 Jun
PMID:Formation of an active form of the interleukin-2/15 receptor beta-chain by insertion of the intracisternal A particle in a radiation-induced mouse thymic lymphoma and its role in tumorigenesis. 1276 10

The MITF/TFE subfamily of basic helix-loop-helix leucine-zipper (bHLH-LZ) transcription factors consists of four closely related members, TFE3, TFEB, TFEC and MITF, which can form both homo- and heterodimers. Previously, we demonstrated that in t(X;1)(p11;q21)-positive renal cell carcinomas (RCCs), the TFE3 gene on the X chromosome is disrupted and fused to the PRCC gene on chromosome 1. Here we show that in t(6;11)(p21;q13)-positive RCCs the TFEB gene on chromosome 6 is fused to the Alpha gene on chromosome 11. The AlphaTFEB fusion gene appears to contain all coding exons of the TFEB gene linked to 5' upstream regulatory sequences of the Alpha gene. Quantitative PCR analysis revealed that AlphaTFEB mRNA levels are up to 60-fold upregulated in primary tumor cells as compared with wild-type TFEB mRNA levels in normal kidney samples, resulting in a dramatic upregulation of TFEB protein levels. Additional transfection studies revealed that the TFEB protein encoded by the AlphaTFEB fusion gene is efficiently targeted to the nucleus. Based on these results we conclude that the RCC-associated t(6;11)(p21;q13) translocation leads to a dramatic transcriptional and translational upregulation of TFEB due to promoter substitution, thereby severely unbalancing the nuclear ratios of the MITF/TFE subfamily members. We speculate that this imbalance may lead to changes in the expression of downstream target genes, ultimately resulting in the development of RCC. Moreover, since this is the second MITF/TFE transcription factor that is involved in RCC development, our findings point towards a concept in which this bHLH-LZ subfamily may play a critical role in the regulation of (aberrant) renal cellular growth.
Hum Mol Genet 2003 Jul 15
PMID:Upregulation of the transcription factor TFEB in t(6;11)(p21;q13)-positive renal cell carcinomas due to promoter substitution. 1283 90

Smokeless tobacco usage is a growing public health concern in the United States. Epidemiological evidence shows a correlation between use of chewing tobacco, lesions of the oral cavity and the incidence of oral and other cancers. However, the molecular mechanism(s) underlying the oral cancer causation are yet unknown. The major constituents of tobacco are known to cause inflammation, DNA damage and cell death. We propose modulation of inflammatory mediators by smokeless tobacco as a novel mechanism for the development of oral cancer. Exposure of hamster cheek pouches to smokeless tobacco extract (STE) results in cleavage of the anti-inflammatory peptide from the anti-inflammatory protein annexin I. Annexin I is produced from cultured oral epithelial cells and its expression is modulated by STE. We further show that STE exposure of oral epithelial cells results in upregulation of the pro-inflammatory protein COX-2. COX-2 is also upregulated in immortalized human oral epithelial cells, human squamous cell carcinoma cells and in primary tumor tissues from head and neck cancer. In summary, we find that exposure to smokeless tobacco results in loss of the anti-inflammatory activity of annexin I and upregulation of the pro-inflammatory COX-2 in oral cells. The dual effect of these regulatory events leads the cells down the carcinogenic pathway.
Mol Cell Biochem 2003 Jun
PMID:Modulation of annexin I and cyclooxygenase-2 in smokeless tobacco-induced inflammation and oral cancer. 1287 Jun 56


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