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)

A prospective, longitudinal study was performed to test the hypothesis that environmental factors (e.g., diet or cigarette smoking) modulate genetic damage caused by treatment for breast cancer and render these women more susceptible to developing second malignancies. A total of 107 women (49 with breast cancer, 52 with benign breast masses, and 6 normal women) were enrolled. This report describes initial studies at the time of enrollment and disease presentation. Mutant frequency at the hprt locus and cloning efficiency of peripheral blood lymphocytes did not differ significantly among the 3 groups. Mutant frequency increased with age, with a history of cigarette smoking, and with the number of years that current smokers used cigarettes. There was no correlation in women with benign masses between mutant frequency and the incidence of chromosome aberrations (28 women) or sister chromatid exchanges (23 women). A maternal history of breast cancer did not influence mutant frequency. There was no significant relationship between dietary intake of vitamins A, B12, C and E, folacin, selenium, calcium, caffeine, or multivitamin pills, and mutant frequency. Serum folate levels in the deficient range were associated (P = 0.02) with elevated mutant frequencies, whereas SCE rates inversely correlated with serum vitamin B12 levels. These results confirm the importance of age and, less so, cigarette smoking as factors that influence mutant frequency and suggest that a micronutrient, folic acid, may modify genetic damage at the hprt locus. To the extent that somatic mutation contributes to carcinogenesis, these environmental factors may enhance the risk of developing malignant transformation.
Environ Mol Mutagen 1992
PMID:Factors influencing mutation at the hprt locus in T-lymphocytes: studies in normal women and women with benign and malignant breast masses. 160 Sep 53

Helicases are essential to both DNA replication and transcription because they separate double-stranded DNA, preparing the single strands for replication or transcription. Because the anti-cancer anthracycline antibiotics stabilize double-stranded DNA primarily by their intercalative binding, we expected the intercalated antibiotics to interfere with helicase action. We examined anthracycline antibiotic effects on SV40 large T antigen helicase activity, using a duplex DNA helicase substrate of 32P-labeled 17-mer annealed to complementary M13mp19(+) circular single-stranded DNA. The T antigen helicase activity was potently inhibited by the anthracycline antibiotics. The T antigen helicase IC50 values for the anthracycline antibiotics were as follows: nogalamycin, 2 x 10(-7) M; daunorubicin, 4 x 10(-7) M; doxorubicin, 4 x 10(-7) M; idarubicin, 1.8 x 10(-6) M; 4'-epidoxorubicin, 2 x 10(-6) M; aclacinomycin, 4 x 10(-6) M; and menogaril, 6 x 10(-6) M. Partially purified helicases from HeLa cells and murine mammary carcinoma FM3A cells also were potently inhibited by doxorubicin, with IC50 values of 4 x 10(-7) M and 9 x 10(-7) M, respectively. Because the abundance, specificities, and types of helicases vary in the cell, this site of action for anthracycline antibiotics may help explain anthracycline potency, drug specificity for DNA or RNA inhibition, and some types of cellular resistance to these drugs.
Mol Pharmacol 1992 Jun
PMID:Helicase inhibition by anthracycline anticancer agents. 161 15

The effects of the transforming growth factor-beta 1 (TGF-beta 1) and epidermal growth factor (EGF) on the growth of cells from 2 endometrial cancer lines, Ishikawa and HEC-50 were evaluated by measuring rates of DNA synthesis and changes in cell numbers during culture. EGF at 17 and 1.7 nM concentrations consistently enhanced HEC-50 cell proliferation. TGF-beta 1 inhibited Ishikawa cell proliferation but, unexpectedly for epithelium-derived cells, stimulated HEC-50 cell growth. This effect is of interest as it indicates that endometrial cells can acquire an altered responsiveness to a growth inhibitor during the process of malignant transformation. Northern blot analyses showed expression of TGF-alpha, TGF-beta 1 and EGF receptors mRNA in both cell lines. Neither estradiol (E2) nor 4-hydroxytamoxifen (OHTam) affected mRNA levels for either TGF-alpha or TGF-beta in HEC-50 cells, a line unresponsive to E2 for proliferation. In Ishikawa cells, previously shown to respond to both E2 and OHTam by increasing proliferation rates, E2 increased TGF-alpha mRNA and reduced TGF-beta mRNA levels. OHTam lowered the levels of both mRNA species, although the effect was greater on TGF-beta than TGF-alpha mRNA. These data are consistent with, but do not prove, the existence of a possible autocrine regulation by TGF-alpha and TGF-beta of human cancer cell proliferation, which might be under E2 influence in Ishikawa cells.
J Steroid Biochem Mol Biol 1992 Jun
PMID:Effects of transforming growth factors and regulation of their mRNA levels in two human endometrial adenocarcinoma cell lines. 161 74

The National Biotherapy Study Group (NBSG) conducted a broad phase II trial using interleukin-2 (IL-2) by continuous infusion and alpha interferon (IFN) subcutaneously in 267 patients with a variety of advanced cancers, including 29 with breast cancer, 89 with renal cancer, and 69 with melanoma. IL-2 [18 million international units (MIU)/m2] was given by continuous infusion for 108 hours with 3 mu/m2 subcutaneous IFN every other day during the IL-2 infusion. The patients were treated for 1 week followed by a 2-week rest. After two cycles of treatment, patients were evaluated for response. Of the 237 patients evaluable for response, 20 (8%) had a complete or partial response and 128 (54%) were stable. Therefore, 62% of the evaluable patients were nonprogressive during the first 90 days of IL-2/IFN therapy. The objective response rate was 11% in melanoma, 7% in renal cancer, 14% in breast cancer, and 3% in patients with a variety of malignancies for an overall response rate of 7% in these patients with advanced cancer. The patients were treated on a general medical ward and tolerated treatment well with fatigue and fever being nearly universal. Dyspnea, pruritus, chills, and elevated creatinines were frequent but less common. This combination biotherapy regimen has minimal activity in a variety of advanced cancers and must be compared with the best existing chemotherapy for each cancer type in randomized, prospective trials.
Mol Biother 1992 Mar
PMID:Combination biotherapy utilizing interleukin-2 and alpha interferon in patients with advanced cancer: a National Biotherapy Study Group Trial. 162 72

The protein-bound polysaccharide of Coriolus versicolor QUEL (PS-K) has been found to express antioxidant activity as an "ion-radical scavenger" in diamine oxidation reactions. The mode of this expression was examined to determine whether the drug functioned as a simple radical scavenger or mimicked the action of superoxide dismutase (SOD). The latter was confirmed in both enzymatic and nonenzymatic superoxide anion radical (O2-.) producing systems in vitro. The SOD mimetic activity of PS-K was demonstrated by quantitative analysis of hydrogen peroxide as the end product of O2-., its formation being assisted catalytically by SOD or PS-K. Analysis by electron spin resonance also confirmed the SOD mimetic activity of PS-K in a xanthine-xanthine oxidase reaction. Relative SOD activity with PS-K was approximately 1/8,000 in a KO2-O2-.-producing system. The SOD mimetic activity of PS-K resisted treatment by 0.7N HCl, 0.7N NaOH, boiling for 30 minutes in a double water bath, and digestion by pronase. Fractionation according to differences in molecular mass caused no significant increase in relative SOD activity within a certain range of molecular mass, indicating that there is no definite molecule expressing SOD mimetic activity. Tumor-bearing rats and human patients with digestive tract cancer who suffered from oxidative stress were relieved by a single intraperitoneal administration of PS-K or a 1-day peroral prescription.
Mol Biother 1992 Mar
PMID:Mimicking of superoxide dismutase activity by protein-bound polysaccharide of Coriolus versicolor QUEL, and oxidative stress relief for cancer patients. 162 73

O4-Alkyldeoxythymidines have been extensively studied for their ability to cause mutations and to induce cancer. Since these adducts can change DNA conformation, they may also have a more immediate effect of altering DNA-protein interactions. To address this issue, the effects of these adducts on restriction enzyme activity were examined. Oligodeoxyribonucleosides containing O4-ethyldeoxythymidine (O4-EtdT) or O4-methyldeoxythymidine (O4-MedT) at a unique site within the sequence 5'-GAATGGATCCTAATGAGATC-3' were constructed by automated DNA synthesis. This sequence contains the recognition site for various restriction enzymes. These oligomers were annealed to various complementary strands and digested with restriction enzymes: BamHI or BstI (GGATCC); Sau3A, NdeII, or MboI (GATC); DpnI (GmATC); and BstYI, MflI, or XhoII (PuGATCPy). Analysis of the digests demonstrated that the presence of either O4-EtdT or O4-MedT abolished the ability of XhoII, MboI, MflI, or NdeII to cut at the restriction site. DpnI failed to cut any of the oligomers. BamHI, Sau3A, BstI, and BstYI exhibited alterations in cutting specificity depending upon the oligomers used. These results demonstrated that O4-alkyldeoxythymidine adducts alter DNA-restriction enzyme interactions in a protein- and sequence-dependent manner. Because of the importance of natural methylation in genetic regulation, it is possible that aberrant methylation in the form of DNA adducts could also alter protein-DNA interactions in cells exposed to DNA-modifying agents.
Mol Carcinog 1991
PMID:Alterations in DNA-restriction enzyme interactions by O4-alkyldeoxythymidines. 164 73

Mutations within the tumor suppressor genes Rb-1 and p53 are commonly found in many human malignancies, and loss of wild-type function of both p53 and RB appear to be important events in the development of these malignancies. Interference with normal RB and p53 function in the cell has apparently also been exploited by the oncogenic genital human papillomaviruses (HPVs), which encode transforming proteins capable of binding cellular RB and p53 proteins. We have investigated the expression of RB and p53 in a series of eight cervical carcinoma cell lines, six of which contain HPV sequences and two of which have arisen apparently independently of HPV infection. In the six HPV-positive lines, no evidence of abnormal RB or p53 protein could be detected. However, there was evidence for abnormal RB and p53 in the two HPV-negative lines. These data are consistent with the hypothesis that loss of wild-type RB and p53 function is necessary for tumor development and that such loss can occur either by mutation within the cellular gene or by expression of viral proteins capable of complexing wild-type cellular proteins.
Mol Carcinog 1991
PMID:Expression of RB and p53 proteins in HPV-positive and HPV-negative cervical carcinoma cell lines. 164 61

Chromosomal abnormalities affecting proto-oncogenes are frequently detected in human cancer. Oncogenes of the myc family are activated in several types of tumors as a result of gene amplification or chromosomal translocation. We have recently found the L-myc gene involved in a gene fusion in small-cell lung cancer (SCLC). This results in a chimeric protein with amino-terminal sequences from a novel gene named rif joined to L-myc. Here we present a preliminary structural characterization of the rlf-L-myc fusion gene, which has been found only in cells with an amplified L-myc gene. In addition, we have used somatic cell hybrids to assign the normal rlf locus to the same chromosome (chromosome 1) on which L-myc resides. Finally, we have been able to establish a physical linkage between rif and L-myc with pulsed-field gel electrophoresis. Our results demonstrate that normal rlf and L-myc genes are separated by less than 800 kb of DNA. Thus, the rlf-L-myc gene fusions are due to similar but not identical intrachromosomal rearrangements at 1p32. The presence of independent genetic lesions that cause the formation of identical chimeric rlf-L-myc proteins suggests a role for the fusion protein in the development of these tumors.
Mol Cell Biol 1991 Aug
PMID:Intrachromosomal rearrangements fusing L-myc and rlf in small-cell lung cancer. 164 86

Male transgenic mice that carry a construct containing 5'-flanking sequences of the gp91-phox gene linked to the early region of the simian virus 40 (SV40) genome reproducibly develop tumors arising from the prostate gland. As gp91-phox is expressed exclusively in terminally differentiating hematopoietic cells of the myelomonocytic lineage, the induction of tumors arising from the prostate gland was unexpected. These lesions appear to be due to a novel transcription signal that was generated during the construction of the transgene. Surprisingly, the histopathological and biochemical properties of the tumor are diagnostic of neuroblastoma rather than of adenocarcinoma of the prostate gland. Tumors produce SV40 T antigen and isoforms of neural cell adhesion molecule characteristic of neuronal cells, and they occur in a testosterone-independent manner. Microscopic examination of prostate glands from young transgenic mice reveals the presence of small lesions arising outside of the prostate gland epithelium, which is consistent with the diagnosis of neuroblastoma and further distinguishes this tumor from prostatic adenocarcinoma. Prostate gland tumors occur in all male animals of susceptible lines carrying the gp91-phox promoter/SV40 early-region transgene. However, variability in the time at which gross tumors appear and the presence of cells expressing T antigen prior to tumorigenesis suggest that somatic events in addition to T-antigen production are required for the development of a malignancy. The extraordinary restriction of the site of tumorigenesis in these animals indicates the presence in the prostate gland of a novel, tissue-specific neuroectodermal cell of origin. These transgenic animals provide a model system for the study of neuroectodermal malignancies.
Mol Cell Biol 1991 Sep
PMID:Restriction of neuroblastoma to the prostate gland in transgenic mice. 165 58

Estradiol-17 beta (E2) is converted exclusively to intracellular metabolites, termed lipoidal estrogens [long chain fatty acid 17 beta-esters (E2-L)], by human mammary cancer tissue and cell lines. In order to further evaluate the biological role of lipoidal estrogens, rates of saturation of the estrogen receptor (ER) along with formation of [3H]E2-L have been measured in human mammary cancer cells exposed to 5 nM [3H]E2. Extensive specific binding of E2 to ER in MCF-7 cells (approximately 37%) and ZR-75-1 cells (approximately 62%) occurred before appreciable synthesis of E2-L was evident and the maximum level of E2-L attained was only 3-9% of the E2 specifically bound to ER. In these ER positive cell lines, and in the ER negative cell line MDA-MB-231, an initial rise in the rate of E2-L formation was followed by a decrease at approximately 6 min and re-establishment of a new rate, indicating turnover of the E2-L fraction by esterification-de-esterification reactions. This data does not support the concept that E2-L acts in the transport of E2 to nuclear receptors, but rather than liberation of E2 from E2-L could serve to maintain occupancy of ER necessary for initiation of DNA synthesis. The esterase, as studied in pooled human mammary cancer tissue, was found to hydrolyse E2-17 beta-long chain fatty acid esters at different rates--the enzyme being less active towards E2-17 beta-stearate compared to E2-17 beta-oleate, -linoleate and -linolenate. Esterase activity was significantly higher in MDA-MB-231 cells compared to MCF-7 cells. Treatment of MCF-7 cells with E2 did not alter the specific activity of the esterase towards E2-17 beta-oleate as substrate. Similarly, addition of dibutyryl c-AMP to ZR-75-1 cell cultures was without effect on E2-L, both during the time when E2-L was accumulating, or during a subsequent phase when E2-L was decreasing following transfer to medium lacking E2. Calcitonin, which increases endogenous c-AMP in MCF-7 cells, had no effect on E2-L in this latter phase using this cell line. Thus, no evidence could be provided that the esterase was under E2 control, or control by polypeptide hormones which utilize c-AMP as a second messenger.
J Steroid Biochem Mol Biol 1991 Nov
PMID:Metabolism of lipoidal derivatives of estradiol-17-beta in human mammary cancer tissue and cell lines. 165 70


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