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The molecular mechanisms underlying premalignant gastrointestinal diseases, such as ulcerative colitis and Barrett's esophagus, remain unknown. For this reason, the expression of the protooncogene c-Ha-ras was studied in ulcerative colitis and Barrett's esophagus. Total cellular RNA was extracted from different regions of the gastrointestinal tract in these two diseases. Expression of c-Ha-ras was greater in proximal than in distal colon and undetectable in Barrett's esophagus. These regional differences in expression were not seen with the control gene beta-actin or with the protooncogenes c-myc and p53. In order to evaluate structural factors contributing to expression, amplification and methylation of c-Ha-ras DNA were studied in these tissues by Southern and slot blotting. No amplification of c-Ha-ras or six other protooncogenes was detected. These data suggest tissue-specific regulation of c-Ha-ras expression in the gastrointestinal tract in certain premalignant disease states.
Exp Mol Pathol 1989 Dec
PMID:Tissue-specific expression of c-Ha-ras in premalignant gastrointestinal mucosae. 255 32

The concomitant expression of certain oncogenes can transform normal diploid rodent cells into transplantable tumorigenic cells. The mechanism by which these oncogenes collaborate is unclear. Recent findings (M. Oshimura, T. M. Gilmer, and J. C. Barrett, Nature [London] 316:636-639, 1985) raise the possibility that karyotypic changes, including monosomy for chromosome 15, are required to induce tumorigenicity in Syrian hamster embryo cells transfected in vitro with v-Ha-ras and v-myc DNAs. We studied the effect of the oncogenes v-Ha-ras and v-myc, introduced by viral infection, on murine hematopoietic cells. The induction of growth factor independence by the two oncogenes was used as an in vitro correlate of tumorigenicity. After a period of reduced growth rate reminiscent of the growth rate of cells in crisis, the doubly infected cells became growth factor independent. These cells showed a great variability in their karyotypes.
Mol Cell Biol 1986 Oct
PMID:Coinfection with viruses carrying the v-Ha-ras and v-myc oncogenes leads to growth factor independence by an indirect mechanism. 354 May 94

A soluble enzyme system has been prepared from a phage P4-infected Escherichia coli strain that supports the replication of exogenous, supercoiled P4 DNA. This DNA synthesis in vitro depends upon the four deoxyribonucleotides and ATP, but is enhanced about four- to fivefold by the presence of other ribonucleotides. E. coli DNA polymerase III holoenzyme, the E. coli single-strand DNA binding protein, and the partially purified P4 alpha gene product are required for replication in vitro. Rifamycin does not inhibit P4 replication in vitro. Since the P4 alpha gene codes for a rifamycin-resistant RNA polymerase (Barrett et al., 1983), and since P4 DNA replication is independent of the host primase (Bowden et al., 1975), we believe the alpha gene product is functioning as a P4-specific DNA primase.
J Mol Biol 1985 Apr 20
PMID:The replication of bacteriophage P4 DNA in vitro. Partial purification of the P4 alpha gene product. 387 88

From the above discussion it is quite obvious that the bioenergetics in helminths are different in many ways from those found in higher organisms. All adult helminths appear to be able to consume oxygen when it is available but none of them can use it to drive the pathways of complete substrate degradation, like typical aerobic organisms, as a major strategy for energy generation. These properties hold also true for those worms residing in a highly aerobic environment, such as the blood stream or the muscle and lung tissues. Although in a number of recent studies oxygen was found to play apparently a greater role in the bioenergetics of adult helminths than originally thought, energy-generating mechanisms in adult worms seem to place greater emphasis on fermentations and anaerobic electron transport processes. These exhibit relatively low energy conservation efficiencies and result in the formation of a variety of organic end products, most of which must be excreted. The obvious correlation between the type of bioenergetic strategy operative in a particular helminth species and its environmental conditions is not well understood. The increased capacity to generate chemical energy and key metabolites of helminths possessing multiple fermentations and anaerobic respirations may give the organism greater versatility and metabolic flexibility to respond to the environmental changes observed in its corresponding habitat. Other helminths, such as schistosomes and filariids, which have continuous access to a fairly constant nutrient supply, were found to depend primarily on the more inefficiently functioning and primitive strategy of glycolysis for energy production. The reason for the occurrence in helminths of limited oxidative capacities is not completely clear. It may be assumed that the variety of alternative anaerobic pathways have evolved in response to the lack of a circulatory system and/or to the specific, often peculiar, environmental conditions prevailing in most parasitic habitats. An alternative idea put forward by Barrett [8] is that helminth metabolism represents a form of biochemical economy. Most endoparasites have an abundant supply of food and swim as if in a land of Cockain, obviously without any need to extract a maximum amount of chemical energy from the nutrients they take up. On the other hand, the fact that free-living and other larval or juvenile stages of helminths often have a typical aerobic bioenergetic pattern is a clear indication that the DNA of these organisms carries the genetic message for all the enzymes involved in complete substrate degradation.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Biochem Parasitol 1985 Oct
PMID:The strategies of energy conservation in helminths. 390 98

Analysis of the role of gene mutations in the multistep process of neoplastic transformation requires that the discrete steps in carcinogenesis first be dissected. Toward this end, we have isolated and characterized preneoplastic Syrian hamster cells which exhibit in vitro a trait highly correlated with neoplastic conversion in vivo. Previous findings (J. C. Barrett, Cancer Res. 40:91-94, 1980) indicate that spontaneous neoplastic transformation of Syrian hamster cells occurs in at least two steps. An intermediate stage, characterized by an aneuploid established cell line which has a propensity to become neoplastic spontaneously upon further growth in vitro, has been described. These preneoplastic cells differ from diploid early-passage Syrian hamster cells in becoming capable of anchorage-independent growth in semisolid agar, as well as becoming neoplastic in vivo when attached to a solid substrate. Evidence presented here demonstrates that anchorage-independent conversion in vitro is a reliable marker for neoplastic conversion in this cell system. Fluctuation analyses, patterned after those described by Luria and Delbruck for microbial genetics, demonstrate that anchorage-independent variants are generated randomly from clonally derived preneoplastic cells at the rate of 10(-8) to 10(-7) variants per cell per generation. These results establish a multistep stochastic process for transformation in vitro and indicate that conversion to anchorage independence may be necessary for Syrian hamster cells to become tumorigenic. The possible role of gene mutation in this step during neoplastic progression is discussed.
Mol Cell Biol 1983 May
PMID:Neoplastic conversion of preneoplastic Syrian hamster cells: rate estimation by fluctuation analysis. 686 45

The polyomavirus late polyadenylation signal is used inefficiently during the late phase of a productive viral infection. Inefficient polyadenylation serves an important purpose for viral propagation, as it allows a splicing event that stabilizes late transcripts (G. R. Adami, C. W. Marlor, N. L. Barrett, and G. G. Carmichale, J. Virol. 63:85-93, 1989; R. P. Hyde-DeRuyscher and G. G. Carmichael, J. Virol. 64:5823-5832, 1990). We have recently shown that late-strand readthrough transcripts serve as natural antisense molecules to downregulate early-strand RNA levels at late times in infection (Z. Liu, D. B. Batt, and G. G. Carmichael, Proc. Natl. Acad. Sci. USA 91:4258-4262, 1994). Thus, poor polyadenylation contributes to the early-late switch by allowing the formation of more stable late RNAs and by forming antisense RNA to early RNAs. The importance of late poly(A) site inefficiency in the viral life cycle has prompted us to map the cis elements of this site. Since the polyomavirus late site proved a poor substrate for in vitro polyadenylation, we used an in vivo assay which allowed us to map the cis sequences required for its function. In this assay, various fragments containing the AAUAAA and different surrounding sequences were placed 1.4 kb upstream of a second, wild-type signal. The second signal served to stabilize transcripts that are not processed at the upstream site, allowing accurate quantitation of relative poly(A) site use by an RNase protection assay. Processing was primary at the upstream site when a large fragment surrounding the poly(A) signal (50 nucleotides [nt] upstream and 90 nt downstream) was tested in this assay, demonstrating that this fragment contains the essential cis elements. Deletion analysis of this fragment revealed that most but not all upstream sequences can be removed with little effect on polyadenylation efficiency, indicating the absence of a strong stimulatory upstream element. Deletion of all but 25 nt downstream of the AAUAAA reduced polyadenylation activity only by half, demonstrating that processing can occur at this site despite the lack of downstream sequences. Thus, the core cis element for polyadenylation is quite small, with most important cis-acting elements lying within 19 nt upstream and 25 nt downstream of the AAUAAA sequence. This core contains the AAUAAA hexanucleotide, an upstream A/U-rich element, and three identical repeats of a 6-nt sequence, UAUUCA. Polyadenylation was eliminated or greatly reduced when either the AAUAAA or the three repeats were mutated.
Mol Cell Biol 1995 Sep
PMID:Characterization of the polyomavirus late polyadenylation signal. 765 95

The pituitary cell-specific transcription factor Pit-1 has been show to trans-activate expression of the prolactin (PRL) promoter in non-pituitary cells. However, the cyclic AMP response element (CRE)-binding protein CREB is known to play a major role in cell-specific expression of hepatocyte-specific genes. Since the PRL promoter contains an asymmetrical form of a cyclic AMP response element (termed the CLE), we investigated whether CREB could also induce PRL promoter activity in non-pituitary cells. Transient expression in rat glial C6 cells of a constitutively active CREB-VP16 fusion protein strongly trans-activated expression of a co-transfected rat PRL promoter construct, (-187)PRL-CAT. Analysis by 5'-deletion showed that this response requires PRL promoter sequences between positions -113/-75. CREB-VP16 did not stimulate expression in C6 cells of any of three control promoter-CAT constructs, implying that the strong response of the PRL promoter to activated CREB is both promoter-specific, and is not due to non-specific transcriptional effects of the potent VP16 moiety of CREB-VP16. Surprisingly, mutations in the CLE only slightly reduced activation by CREB-VP16 of construct (-204)PRL-CAT, implying that the major action of CREB-VP16 on the PRL promoter does not involve a direct interaction with the CLE. CREB-VP16 stimulated PRL-CAT activity in C6 cells as strongly as, and synergistically with, Pit-1. These results imply that CREB can strongly and specifically activate expression of the PRL promoter in non-pituitary cells, via a mechanism different from that employed by Pit-1.
Mol Cell Endocrinol 1994 May
PMID:A constitutively active form of CREB can activate expression of the rat prolactin promoter in non-pituitary cells. 939 71

The cell undergoes a diverse range of stimulations including growth factor activation and signal transduction from adhesion receptors, such as cadherins. In the absence of a mitogenic signal from outside the cell, beta catenin is sequestered in complexes with the product of the adenomatous polyposis coli (APC) gene and a serine threonine glycogen kinase (GSK 3 beta) enabling degradation of free beta catenin. Residual catenins hold cells together by binding to cadherins both at adherens junctions and the actin cytoskeleton. When a mitotic signal is delivered by the wnt pathway, GSK 3 beta is antagonised so that beta catenin can no longer be degraded. Cytosolic concentrations rise and binding to other newly synthesised proteins occurs, especially transcription factors that are transported to the nucleus, such as lymphocyte enhancing factor and T cell factor. This article discusses the signalling between mitogenic and adhesion pathways and suggests that it is a global mechanism for development, differentiation, and disease. These changes in catenin and APC biology may not be sufficient alone to transform cells fully but they appear to be a necessary final common pathway for several cancers of the mucous secreting crypts (including Barrett's oesophageal lesions and colorectal cancer) or stratified secreting epithelium (melanoma) before invasion.
Mol Pathol 1997 Dec
PMID:Cadherin and catenin biology represent a global mechanism for epithelial cancer progression. 953 77

Villin is a cytoskeletal protein that is involved in the formation of brush-border microvilli in normal small intestine and colon epithelium. This protein is present in Barrett's metaplasia but is reported not to be expressed in Barrett's adenocarcinoma. In this study, we analyzed villin protein expression in Barrett's metaplasia and in both Barrett's adenocarcinomas and tumors of the gastric cardia. Immunohistochemical analysis was used to evaluate the expression and cellular localization of the villin protein in 21 cases of Barrett's metaplasia, 30 cases of Barrett's adenocarcinoma, 16 cases of gastric cardia adenocarcinoma, and eight cases of adenocarcinoma of the distal esophagus. Southern, northern, and western blot analyses were used to evaluate the potential mechanisms for regulation of villin protein expression. Villin protein expression was observed in 21 of 21 cases (100%) of intestinal-type Barrett's metaplasia and in 28 of 30 cases (93%) of Barrett's adenocarcinoma and was thus highly expressed in these tumors. Northern blot analysis demonstrated villin mRNA (3.5 and 2.7 kb) in both villin-positive Barrett's metaplasia and adenocarcinomas. Western blot analysis with the antibody used for immunohistochemical analysis confirmed the presence of a single villin protein band of 95 kDa. Abundant villin expression also was present in both adenocarcinoma of the gastric cardia (13 of 16 cases; 81%) and distal esophageal adenocarcinomas of unknown origin (six of eight cases; 75%). The intestinal brushborder enzyme sucrase isomaltase was found to be present in only 22 of 46 cases (48%) of the adenocarcinomas that expressed villin. We concluded that the protein villin is highly expressed in Barrett's adenocarcinomas and is well maintained in these and other esophageal tumors.
Mol Carcinog 1998 Jul
PMID:Abundant expression of the intestinal protein villin in Barrett's metaplasia and esophageal adenocarcinomas. 968 44

The molecular genetic mechanisms underlying esophageal cancer are poorly understood. However, a novel gene that may be involved in esophageal carcinogenesis was recently localized by others to distal 17q by linkage analysis of kindreds with palmoplantar keratoderma and squamous cell carcinoma of the esophagus. To help determine whether a distal 17q gene may also be involved in the pathogenesis of primary Barrett's esophageal and gastric cardia adenocarcinomas, we performed loss of heterozygosity (LOH) analysis of 21 Barrett's and 18 gastric cardia adenocarcinomas at loci spanning 17q: cen-BRCA1-SSTR2-D17S2058-D17S929-D17S722-+ ++D17S937-D17S802-tel. Over 50% of the Barrett's and cardia adenocarcinomas demonstrated loss of an allele at one or more informative distal 17q markers. One common overlapping region of loss involved loci mapped to distal 17q24-proximal 17q25, which tentatively defines a potential chromosomal region distal to BRCA1 involved in the pathogenesis or progression of both types of adenocarcinomas. LOH analysis of DNA from matched microdissected sections of Barrett's metaplasia suggested that loss of D17S2058 in this region may be an early event in the malignant transformation of Barrett's metaplasia. No statistically significant correlations between 17q LOH and tumor stage or patient survival were noted. In summary, LOH mapping of 17q in Barrett's and cardia adenocarcinomas suggests the existence of at least one putative distal 17q tumor suppressor gene involved in the pathogenesis of these tumors.
Mol Carcinog 1998 Aug
PMID:Distal chromosome 17q loss in Barrett's esophageal and gastric cardia adenocarcinomas: implications for tumorigenesis. 972 14


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