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Transformation of FR3T3 rat fibroblasts by a c-Ha-ras oncogene but not by bovine papillomavirus type 1 is associated with an increase in the abundance of mRNAs from prototype strain MVMp of infecting minute virus of mice, an oncosuppressive parvovirus. This differential parvovirus gene expression correlates with the reported sensitization of ras- but not bovine papillomavirus type 1-transformed cells to the killing effect of MVMp (N. Salomé, B. van Hille, N. Duponchel, G. Meneguzzi, F. Cuzin, J. Rommelaere, and J. Cornelis, Oncogene 5:123-130, 1990). Experiments were performed to determine at which level parvovirus expression is up-regulated in ras transformants. An MVMp "attenuation" sequence responsible for the premature arrest of RNA elongation was either placed or not placed in front of the chloramphenicol acetyltransferase gene and brought under the control of MVMp early promoter P4. Although the MVMp attenuator reduced P4-driven chloramphenicol acetyltransferase expression, the extent of attenuation was similar in normal and ras-transformed cells. Moreover, the analysis of P4-directed viral RNAs in MVMp-infected cultures by RNase protection and nuclear run-on assays also revealed a transcription elongation block of a similar amplitude in both types of cells. In addition, the stabilities of the three major parvoviral mRNAs did not vary significantly between normal and ras-transformed cells. Hence, it is concluded that the ras-induced increase in the accumulation of parvoviral mRNAs is mainly controlled at the level of transcription. Consistently, the TATA motif of the P4 promoter proved to have a differential photoreactivity when tested by in vivo UV footprinting assays in ras-transformed versus normal cells.

Amphiregulin (AR) and cripto are proteins that are structurally related to epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha). AR is also functionally related to this family of growth regulatory molecules and is able to bind and activate the 170-kDa EGF receptor (EGFR). Human EGFR-3 (HER3)/ERBB3 is a recently identified protein related to the EGFR that is widely expressed in breast carcinomas and is a candidate receptor for EGF-like growth factors. Differential expression of these putative ligands and receptors in transformed cells suggests that they may function in an autocrine manner to regulate tumor cell growth. Specific mRNA transcripts for TGF-alpha [4.8 kilobases (kb)], AR (1.4 kb), cripto (2.2 kb), and HER3 (6.2 kb) were expressed in a majority of human colon cancer cell lines. HER3 mRNA was detected in 55% of primary or metastatic human colorectal carcinomas but in only 22% of normal colon mucosa and 32% of normal liver samples. In contrast, cripto and AR mRNA were expressed in 60-70% of primary or metastatic human colorectal cancers but in only 2-7% of normal human colonic mucosa. Immunostaining also detected AR protein in primary and metastatic colorectal tumors but not in normal colon or uninvolved liver. These findings suggest that cripto and AR may be useful markers to discriminate between normal and malignant colonic epithelium and may provide a selective growth advantage for colorectal carcinomas.

Hemostatic control is based in a delicate balance between the activities of activator enzymes and their inhibitors, each one depending on a large number of proteins. Plasma Antithrombin III (ATIII) is one of the most important coagulation inhibitors and the fundamental enzyme for the therapeutical action of heparin. In the last years it was well established that ATIII deficiency accounts for a thrombotic state and inefficiency of heparin therapy. In this work, the authors review the biology of ATIII including its biochemical nature, its physiology, physiopathology and mechanism of action, analysing the implications of its deficiency. The authors draw the attention on clinical and laboratory studies that analyse the prevalence and importance of congenital and acquired deficiency of ATIII, in relation to the prevalence of venous thrombosis. Finally, the laboratory methods applied to the study of ATIII and to the biological control of heparin therapy are described with emphasis on the importance of the ATIII concentrates on this type of treatment. Also the fundamental aspects of heparin resistance are specially mentioned.

Previous emphasis in cancer research has been placed on genes in which activating mutations are found in experimental systems and sometimes in human tumors, and many of these genes are the cellular homologs of retroviral oncogenes. Studies of genes whose functions are necessary for maintenance of the normal cellular state, but for which loss-of-function mutations lead to tumor development, are limited. The latter genes have been variously termed 'tumor suppressor genes', 'recessive oncogenes', and 'anti-oncogenes', and each term defines a specific aspect of their properties and may not always be applicable. The retinoblastoma (RB) gene is the first such gene to be identified, and was isolated based on its chromosome localization and on the recessive nature of the tumor phenotype. That is, both wild type RB alleles must be inactivated in a single cell for neoplastic transformation to occur, and deletions at the chromosomal locus now known to contain RB are often found in retinoblastoma cells. Candidate genes for Wilms' tumor and neurofibromatosis type I have also been identified recently, and loss of function of these genes seems to be indicated for these diseases. Allelic loss of chromosome 17p13 is frequently observed in many tumor types. The p53 gene was mapped to this chromosomal region and has been shown to be a tumor suppressor gene, and germ-line mutations of p53 recently were found to be correlated with Li-Fraumeni syndrome, a syndrome characterized by multiple neoplasms. Rapid progress in studies of tumor suppressor genes points to diverse mechanisms for their functioning in the negative regulation of cell growth. A scenario depicting cell growth control by positive and negative regulators, based on new and emerging findings, is the main focus of this review.

Thirty-three subjects, belonging to a large family with functional antithrombin III (ATIII) deficiency (type IIa) and recurrent thromboembolism, were investigated for ATIII, heparin cofactor II (HCII), protein C (PC) and protein S (PS). We report the exceptional finding of two cases of triple deficiency: ATIII combined with HCII and PC in the first case aged 15 and ATIII combined with HCII and PS in the second case aged 27. Interestingly, both are asymptomatic thus far. Twenty-five other deficient members were found, among which seven are affected with a double deficiency. Totally, the results of our study show 38 deficiencies of four distinct antithrombotic protein: ATIII (n = 9), HCII (n = 9), PC (n = 7) or PS (n = 13). Two types of HCII deficiency were observed and type I PC deficiency was found. Functional PS deficiency was characterized by reduced levels of cofactor activity for activated PC. Our report demonstrates that combined deficiencies should be sought in a family already known to be deficient in one antithrombotic protein.

We have used a previously described cross-linking assay and half-FRT site substrates to examine the requirements for synapsis, strand exchange, and strand scission. The cross-linking assay showed that the minimum functional FRT site needed for synapsis contains two inverted FLP-binding elements surrounding an 8-bp core. This indicates that four FLP molecules interact with four binding elements in a synaptic complex. The analysis using half-sites showed that the enzyme can catalyze efficient strand exchange between a half-site and the intact FRT site. The reaction occurred only if the half-site had at least 2 bp but no more than 4 bp of the adjoining core sequence. The exchange occurred exclusively at the regions of limited core homology between the respective half-site and the FRT site. The absence of strand exchange between an intact site and a half-site bearing regions of core nonhomology indicates that 1 bp of homology is not sufficient for the formation of stable recombinant structures. Qian et al. (X.-H. Qian, R. B. Inman, and M. M. Cox, J. Biol. Chem. 265:21779-21788, 1990) have recently shown that the FLP protein can catalyze the formation of dimeric, trimeric, and tetrameric complexes with half-FRT sites. We show that only half-sites that contained at least 2 bp of adjacent core could form stable dimer products and be cleaved by the enzyme. Stable dimers were formed between a noncleavable half-site and a cleavable half-site, suggesting that only a single cleavage event is needed for the formation of the dimer.

Proteins purified on the basis of their affinity for RNA polymerase II effectively substitute for previously defined transcription initiation factors. In two assays, formation of initiation complexes and transcription in vitro, the RNA polymerase II-associated proteins behaved identically to a fraction containing transcription factors IIE and IIF. Both fractions greatly stabilized the association of polymerase with the promoter and were required for the formation of complete initiation complexes. By using the DNA-cleaving reagent phenanthroline.copper in footprinting reactions, the RNA polymerase II-associated proteins were shown to be required for a DNA conformation change near the initiation site of the promoter. Based on similarity to the prokaryotic transcription complex, this conformation change is likely to represent a transition from a closed to an open complex.

Estrogen and progesterone cytoplasmic receptors (ER, PgR) were determined by radiochemical DCC technique in the endometria of 16 normal women at before child bearing age and 6 to 9 months after LNG IUD insertion. The study showed that both ER and PgR were reduced significantly after LNG IUD insertion (P less than 0.01). The decrease of ER and PgR might play an important role in gland reduction and endometrial atrophy. It may be one mechanism of the contraceptive effect and the cause of anemia or spotting between menstruation during the course of LNG IUD insertion.