Molecular mechanisms of virus-induced carcinogenesis: the interaction of viral factors with cellular tumor suppressor proteins

Accumulating evidence indicates that tumor viruses represent a major etiological factor in a significant portion of human cancers. These cancers include human papillomavirus induced anogenital cancers, hepatitis B and C virus associated hepatocellular carcinomas, nasopharyngeal carcinomas and lymphomas linked to Epstein-Barr virus infection, and human T cell leukemia virus associated adult T cell leukemias. This review summarizes the recent progress made in understanding the molecular mechanisms of viral carcinogenesis, with a particular focus on the interaction of viral factors with cellular tumor suppressor proteins. The functional inactivation of tumor suppressor proteins may represent a common strategy by which several tumor viruses contribute to malignant cell transformation.Abbreviations EBV Epstein-Barr virus - E6AP E6-associated protein - HBV Hepatitis B virus - HCC Hepatocellular carcinoma - HPV Human papillomavirus - HTLV Human T cell leukemia virus - pRb Retinoblastoma protein - RB Retinoblastoma - SV40 Simian virus 40     

多发性骨髓瘤患者血清IL-6活性与急性相蛋白浓度的相关性研究

运用敏感的B_9细胞增殖试验检测了81例多发性骨髓瘤(MM)患者血清IL-6活性,同时分析了标本的几种急性相蛋白含量,结果表明,68％MM患者血清中IL-6活性大于5μ/ml(正常对照为5μ/ml以下),几种急性相蛋白中C-反应性蛋白(CRP)在MM时升高(P<0.01),平均达正常对照组的17倍以上,MM患者补体C_4与正常对照组无差异(p>0.05),C_3、白蛋白及转铁蛋白在MM时分别比正常下降24.42％、38.83％和32.80％,且与疾病分期有关,在血清IL-6大于5μ/ml的55例中,IL-6活性与CRP、C_3、白蛋白的相关系数分别为0.46,-0.34和-0.29,IL-6与转铁蛋白浓度相关不明显。本文结果提示:CRP、C_3及白蛋白等含量的变化可作为反映MM病情的简易而敏感的指标。     

Effect of radioprotectors on cyclic AMP-dependent protein phosphorylation

The ability of radioprotectors (serotonin, aminoethylisothiouronium) in radioprotective doses to stimulate cyclic AMP-dependent phosphorylation of mouse liver cytosol and nuclear and spleen cytosol proteins in vivo was demonstrated. In experiments in vitro, the radioprotectors had no direct action on protein kinase activity or its stimulation by cyclic AMP. It is postulated on the basis of these results and those of previous investigations that activation of cyclic AMP-dependent phosphorylation is due to an increase in the intracellular cyclic AMP concentration under the influence of the radioprotectors.Laboratory of Radiation Biophysics, Department of Biophysics, Biological Faculty, Moscow State University. (Presented by Academician of the Academy of Medical Sciences of the USSR S. E. Severin.) Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 87, No. 3, pp. 230–232, March, 1979.     

Concentrations of serum total protein and protein fractions during diestrus and pregnancy in Makuii ewes

The aim of this study was to determine the blood protein changes during different stages of pregnancy and to compare with prepregnancy diestrus in ewes. A total of 90 blood samples were taken from ten Makuii ewes (the native sheep breed in Iran) at diestrus and on days 8, 14, 28, 45, 60, 90, 125, and 145 of pregnancy. Serum protein electrophoresis of samples exhibited four fractions: albumin, α, β, and γ fractions in Makuii ewes, which in α- and γ-globulin bands were divided to α1 and α2; and γ1 and γ2, respectively. The mean concentrations (in gram per deciliter) of total serum proteins, albumin, α1-, α2-, β-, γ1-, and γ2-globulin at diestrus period were 7.03, 3.77, 0.18, 0.74, 0.41, 1.56, and 0.41, respectively. Those values fluctuated nonsignificantly throughout gestation until the 125th day of pregnancy. Thereafter, a significant decrease (p < 0.01) in serum protein levels occurred at the 145th day of pregnancy compared to prepregnancy and other gestational time points. It was concluded that blood protein levels declined sharply during late gestation when the nutrient demands of the fetus were maximal.     

Synaptophysin: A reliable marker for medulloblastomas

Summary Synaptophysin is an acidic, integral membrane glycoprotein (M_r 38000) of presynaptic vesicles in various neurons and neuroendocrine cells, and in tumours derived from such cells. By indirect immunofluorescence microscopy of cryostat sections, using the monoclonal antibody SY 38 to synaptophysin, a consistent positive immunoreactivity was observed in all medulloblastomas (n= 6) and neuroblastomas (n=3) as well as a ganglioneuroma and a glioneuronal hamartoma. The presence of synaptophysin in medulloblastomas was confirmed biochemically by immunoblotting experiments. For purpose of comparison, the expression of intermediate-sized filament (IF) proteins was also examined. While neurofilament proteins were consistently expressed in the neuroblastomas (3/3), the ganglioneuroma and the glioneuronal hamartoma, IF distribution in medulloblastomas was variable. A neurofilament-positive type of tumour (1/6) could be distinguished from vimentin-expressing neoplasms (4/6) by immunocytochemistry. These data indicate that synaptophysin is a reliable marker for medulloblastomas as well as other differentiated and undifferentiated neuronal tumours and in this respect is superior to the more heterogeneous expression patterns of IF proteins in these tumours.     

胰岛素样生长因子结合蛋白与胰岛素抵抗的关系

胰岛素样生长因子系统是一个由配体、受体、结合蛋白及蛋白酶构成的复杂网络,会受到诸多因子的调节.该系统中的胰岛素样生长因子结合蛋白在不同细胞的增殖和分化中起着重要的作用.临床及体内外研究表明胰岛素抵抗形成过程中,IGFBP出现异常表达.IGFBP通过不同机制抑制或促进胰岛素抵抗的形成.     

The beta1 adrenergic effects of antibodies against the C-terminal end of the ribosomal P2beta protein of Trypanosoma cruzi associate with a specific pattern of epitope recognition

BALB/c mice immunized with recombinant Trypanosoma cruzi ribosomal P2beta protein (TcP2beta) develop a strong and specific antibody response against its 13 residue-long C-terminal epitope (peptide R13: EEEDDDMGFGLFD) that has a concomitant beta1-adrenergic stimulating activity. However, other animals that undergo similar immunizations seem tolerant to this epitope. To evaluate further the antibody response against the ribosomal P proteins, 25 BALB/c and 25 Swiss mice were immunized with TcP2beta. From the 50 animals, 31 developed a positive anti-R13 response, whereas 19 were non-responsive. From the 31 anti-R13 positive mice, 25 had anti-R13 antibodies that recognized the discontinuous motif ExDDxGF, and their presence correlated with the recording of supraventricular tachycardia. The other six had anti-R13 antibodies but with a normal electrocardiographic recording. These anti-R13 antibodies recognized the motif DDxGF shared by mammals and T. cruzi and proved to be a true anti-P autoantibody because they were similar to those elicited in Swiss, but not in BALB/c mice, by immunization with the C-terminal portion of the mouse ribosomal P protein. Our results show that the recognition of the glutamic acid in position 3 of peptide R13 defines the ability of anti-R13 antibodies to react with the motif AESDE of the second extracellular loop of the beta1-adrenergic receptor, setting the molecular basis for their pathogenic beta1 adrenoceptor stimulating activity.     

Structural and functional complexity of the humoral response against the Trypanosoma cruzi ribosomal P2 beta protein in patients with chronic Chagas' heart disease

High levels of antibodies against the C-terminus of the Trypanosoma cruzi TcP2 beta ribosomal protein, defined by the peptide EEEDDDMGFGLFD, named R13, have been measured in sera from patients with chronic Chagas' Heart Disease (cChHD). These antibodies also recognize an epitope on the second extracellular loop of the beta 1-adrenergic receptor, inducing a functional response on cardiomyocytes. The aim of this study was to gain novel insights into the structural basis of this cross-reactivity as well as to evaluate the origin of anti-M2- cholinergic receptor antibodies, which are also commonly found in cChHD patients. To address these questions we immunopurified anti-R13 antibodies and studied the structural requirements of epitope recognition. Results showed that the immunopurified antibodies recognized a conformation of R13 in which the third Glu residue was essential for binding, explaining their low affinity for the mammalian homologue (peptide H13: EESDDDMGFGLFD). Alanine mutation scanning showed individual variations in epitope recognition in each of the studied patients. The importance of a negatively charged residue at position 3 for the recognition of anti-R13 antibodies was further confirmed by competition experiments using a Ser3-phosphorylated H13 analogue, which had 10 times more affinity for the anti-R13 antibody than the native H13 peptide. Moreover, anti-R13 antibodies stimulated either the beta 1-adrenergic or the M2-cholinergic receptor, in strict agreement with the functional properties of the IgG fractions from which they derived, demonstrating that the same parasite antigen may generate antibody specificities with different functional properties. This may be a clue to explain the high variability of electrophysiological disturbances found in cChHD.     

Cytochemical manifestations of short- and long-term activation of the rat brain dopaminergic system

Laboratory of Cytochemistry, Brain Research Institute, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR O. S. Adrianov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 112, No. 7, pp. 41–42, July, 1991.