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Biomedical subjects

A Dejean

Publications and source records attributed to A Dejean.

At least 73 records · Page 4Linked to original sources
PubMed1991

[Hepatitis B virus and hepatocellular carcinoma].

Hepatocellular carcinoma in woodchuck were characterized for woodchuck hepatitis virus integration nea c-myc oncogene. In one tumor, viral integration resulted in overexpression of a c-myc viral cotranscript. In a second tumor, viral insertion, 600 bp upstream of c-myc exon 1, was associated with increased levels of normal c-myc mRNA. These results demonstrate that integration of woodchuck hepatitis virus near a proto-oncogene can contribute to the genesis of liver tumors. From a comparison of a single hepatitis B virus (HBV) integration site in a human hepatoma with the corresponding unoccupied site have shown HBV DNA insertion in a putative cellular exon. This exon presented striking similarity to the DNA-binding domain of the thyroid/steriod hormones receptors. The corresponding cDNA has been isolated (hap gene) as shown to encode the retinoic acid receptor. It is most probable that consequent to HBV insertion, hap gene became inappropriately expressed as an altered chimaeric gene retinoic acid receptor, thus contributing to the cell transformation. As for woodchuck these results strongly support the possibility that HBV, may play a direct role in liver carcinogenesis by insertional mutagenesis.

Amino Acid Sequence↗
PubMed1991

[Biological parameters of the efficiency of retinoic acid in acute leukemia].

We have previously shown that all-trans retinoic acid therapy is an alternative therapy for acute promyelocytic leukemia (AML3) via differentiation of the leukemic cells. The t(15;17) translocation is specifically found in this leukemia. We and others have shown that through this translocation the RAR alpha gene is rearranged and its expression altered in AML3 cells. The gene is truncated and fused to a novel gene (PLM). This results in a fusion protein whose transactivating properties may be implicated in the leukemogenesis of this disease. Retinoic acid cytoplasmic binding proteins (CRABP and CRBP) are not detected by PAGE chromatography in normal or malignant hematopoietic cells. During all-trans RA therapy, a) all-trans RA plasma concentrations are within in vitro differentiating concentration (med. 0.4 microgram/ml); b) increased expression of the normal remaining RAR alpha allele is rapidly observed and may explain the paradoxical induction of RA differentiation in these cells; c) CRABPII is induced in the bone marrow cells of AML3 patients and remains detectable 1 month after withdrawal of RA. AML3 in relapse after RA therapy is always less sensitive to RA in vitro and in vivo. Our data suggest that modification of the metabolisation pathways of RA may be one of parameters linked to this resistance. It appears that the efficacy of all-trans RA is the resultant of multiple parameters (RA concentration, ratio of PML/RAR alpha transcripts to normal RAR alpha, CRABP) which need to be defined to efficiently monitor all-trans RA therapy in APL.

Drug Administration Schedule↗
PubMed1990

The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus.

Retinoic acid is a vitamin A derivative with striking effects on development and cell differentiation. Several nuclear retinoic acid receptors (RARs), acting as ligand-inducible transcription factors, have been characterized and indirect evidence suggests that they have distinct roles. One of the most intriguing properties of retinoic acid is its ability to induce in vivo differentiation of acute promyelocytic leukaemia (APL) cells into mature granulocytes, leading to morphological complete remissions. Because the RAR alpha gene maps to chromosome 17q21 (ref. 14), close to the t(15;17) (q21-q11-22) translocation specifically associated with APL, we analysed RAR alpha gene structure and expression in APL cells. We report here that, in one APL-derived cell line, the RAR alpha gene has been translocated to a locus, myl, on chromosome 15, resulting in the synthesis of a myl/RAR alpha fusion messenger RNA. Using two probes located on either side of the cloned breakpoint, we have found genomic rearrangements of one or other locus in six patients out of eight, demonstrating that the RAR alpha and/or myl genes are frequently rearranged in APL and the breakpoints are clustered. These findings strongly implicate retinoic acid receptor alpha in leukaemogenesis.

Base Sequence↗
PubMed1990

Identification of a retinoic acid responsive element in the retinoic acid receptor beta gene.

Retinoic acid, the first morphogen described so far in vertebrates, is a vitamin A derivative which exerts striking effects on development and differentiation. The identification of three retinoic acid receptors as members of the nuclear receptor super-family provides an explantation for the molecular action of morphogens on gene expression. Functional analysis of the receptors requires the identification of target genes and of their cis-acting retinoic acid-responsive elements. We have previously shown that the retinoic acid receptor beta gene is transcriptionally up-regulated by retinoic acid and now report the characterization of a functional retinoic acid responsive element in the beta gene that mediates trans-activation by retinoic acid. Using deletion mapping, we have identified a 27-base pair fragment, located 59 base pairs upstream of the transcriptional start, which confers retinoic acid responsiveness on the herpes virus thymidine kinase promoter. This sequence contains a perfect direct repeat of the motif GTTCAC, which is reminiscent of the 5' half-palindrome of the thyroid and oestrogen hormone responsive elements. Specific binding of the beta protein to the retinoic acid responsive element is demonstrated and is independent of the presence of retinoic acid. Both alpha and beta receptors enhance retinoic acid response in CV1 cells, indicating that they can both act through the same DNA sequence.

Base Sequence↗
PubMed1990

The retinoic acid receptors.

Three retinoic acid receptors (RAR), structurally homologous to steroid and thyroid hormone nuclear receptors, have recently been cloned. Analysis of the tissue distribution of RARs mRNAs have demonstrated a distinct expression pattern of the receptors' transcripts. Moreover, the RAR beta gene specifically, is autoregulated by RA. These findings suggest that the retinoic acid receptors differentially contribute retinoic acid physiology.

Animals↗
PubMed1990

Hepatitis B virus as an insertional mutagene in a human hepatocellular carcinoma.

Chronic hepatitis B virus (HBV) infection is etiologically related to human hepatocellular carcinoma (HCC). Most HCCs contain integrated HBV DNA in the liver cellular DNA, suggesting that the integration may be involved in carcinogenesis. From a comparison of a single HBV integration site present in a hepatoma with the corresponding unoccupied site in the non-tumourous tissue of the same liver, we have shown that HBV DNA inserted in a putative cellular exon with striking similarity to the DNA-binding domain of the thyroid/steroid hormone receptors. The corresponding cDNA has been isolated (hap gene) and shown to encode the retinoic acid receptor. In the original patient, integration took place so that the first codons of the viral surface protein gene became fused in frame with most of the hap gene. Because retinoic acid is known to regulate the transcription of target genes crucial for cellular growth and differentiation, it is most probable that consequent to the HBV insertion, hap, usually transcribed at a very low level in normal hepatocytes, became inappropriately expressed as an altered chimaeric retinoic acid receptor, thus contributing to the cell transformation. These results strongly support the possibility that HBV may play a direct role in liver carcinogenesis by insertional mutagenesis.

Amino Acid Sequence↗
PubMed1990

The retinoic acid receptor alpha gene is rearranged in retinoic acid-sensitive promyelocytic leukemias.

All-trans retinoic acid (RA), the active metabolite of vitamin A, has recently been demonstrated to be an efficient alternative to chemotherapy in the treatment of acute promyelocytic leukemia (M3 subtype of the French-American-British cytological classification). Complete remission is obtained by inducing terminal granulocytic differentiation of the leukemic cells. To elucidate whether the effect of retinoic acid on the differentiation of M3 leukemic cells was related to any specific characteristics of its receptor, we analyzed the structure and expression of retinoic acid receptor (RAR) genes in 16 M3 patients. Abnormal RAR alpha transcripts were detected in 13 cases. In nine patients, the genomic DNA was analyzed by Southern blotting and evidence for a rearranged RAR alpha gene was found generated in four cases. Normal RAR transcripts and germline restriction fragments were found in samples from normal or other leukemic cells, suggesting that this alteration of the RAR alpha gene is specifically seen in M3 leukemias. These results suggest that alteration of the retinoic acid receptor alpha may be implicated in M3 leukemogenesis.

Adult↗
PubMed1989

Differential expression and ligand regulation of the retinoic acid receptor alpha and beta genes.

Retinoic acid (RA) is a vitamin A derivative that exhibits major effects on biological processes such as cell differentiation and embryo pattern formation. Two human retinoic acid receptors (RAR alpha and beta) have been recently characterized. These receptors are encoded by two genes and their affinities for RA differ, suggesting that these two nuclear receptors may have distinct roles in mediating the varied biological effects of RA. Here we show that RAR alpha and beta differ in the regulation of expression of their mRNAs. Different levels of RAR alpha and beta transcripts were found in the various human tissues analysed. In addition, treatment of human hepatoma cells with RA leads to a rapid 10- to 50-fold increase in RAR beta mRNA levels, whereas RAR alpha mRNA expression is not affected. The induction of RAR beta transcription does not require de novo protein synthesis but is completely abolished by inhibitors of RNA synthesis. Nuclear transcript elongation assays indicate that the mechanism of RAR beta mRNA induction lies at the transcriptional level. These data demonstrate that the RAR beta gene is a primary target for RA. The differences in regulation of RAR gene expression might be a fundamental aspect of retinoid physiology and may prove especially important in the analysis of the morphogenic properties of RA.

Carrier Proteins↗
PubMed1988

Identification of a second human retinoic acid receptor.

We have previously described a human complementary DNA that encodes a novel protein which is homologous to members of the steroid/thyroid nuclear receptor multigene family. This novel protein (hap for hepatoma) exhibits strong homology with the human retinoic acid receptor (RAR) which has been recently characterized. To test the possibility that the hap protein might also be a retinoid receptor, a chimaeric receptor was created by replacing the putative DNA binding domain of hap with that of the human oestrogen receptor (ER). The resulting hap-ER chimaera was then tested for its ability to trans-activate an oestrogen-responsive reporter gene (vit-tk-CAT) in the presence of possible receptor ligands. Here we show that retinoic acid (RA) at physiological concentrations is effective in inducing the expression of this reporter gene by the hap-ER chimaeric receptor. This demonstrates the existence of two human retinoic acid receptors designated RAR-alpha and RAR-beta.

Amino Acid Sequence↗
PubMed1985

Experimental studies on the replication and dissemination of Qalyub virus (Bunyaviridae: Nairovirus) in the putative tick vector, Ornithodoros (Pavlovskyella) erraticus.

A study was undertaken to determine if the argasid tick, Ornithodoros (Pavlovskyella) erraticus, can serve as a biological vector of Qalyub (QYB) virus. The suckling mice used as viremic vertebrate hosts were acceptable hosts for all feeding stages of this tick and developed relatively high titered viremias (4.4-6.5 log10PFU/ml) 24-120 hr post intracerebral inoculation. Larval, nymphal, and adult ticks became orally infected with QYB virus after ingesting 4.4-6.4 log10PFU/ml. The overall infection rate for all experiments was 67/205 and virus was recovered up to day 179 postfeeding. Incubation of known quantities of QYB virus with uninfected triturated tick tissues did not result in any appreciable virus inactivation. QYB viral antigen was detected by immunofluorescence primarily in the tick midgut posterior diverticula cells. First and second instar nymphs orally infected as larvae did not individually transmit QYB virus to suckling mice; however they successfully transmitted the virus when feeding in groups of 11-20 per mouse. Three out of fourteen of the orally-infected male and female ticks individually transmitted QYB virus orally to suckling mice. Organ titrations of ticks orally exposed to QYB virus demonstrated virus primarily in midgut tissues; dissemination to other organ systems was discovered in only 1 tick after 142 days extrinsic incubation. Vertical transmission of virus from infected female ticks to progeny was not demonstrated. Four of the 39 ticks in our colony were infected with a spirochete; presumably, Borrelia crocidurae. O. (P.) erraticus apparently satisfies the conditions that would implicate this species as a biological vector of QYB virus and is the only known arthropod from which this virus has been isolated in nature.

Animals↗
PubMed1984

Specific hepatitis B virus integration in hepatocellular carcinoma DNA through a viral 11-base-pair direct repeat.

Integrated hepatitis B virus (HBV) DNA sequences have been cloned from cellular DNA of two human liver tumors. The structure of the clones was determined by restriction mapping, and the host-viral DNA junctions were sequenced. In each clone one junction mapped to within an 11-base-pair sequence, 5' T-T-C-A-C-C-T-C-T-G-C, which is directly repeated near the extremities of the cohesive-end region of the free viral genome. The two copies of this sequence are termed DR1 and DR2. While one clone carried a host-viral junction within DR1, the second one carried a host-viral junction within DR2. The first 1 or 2 base pairs of the repeat were deleted upon recombination with the host genome, leaving at the junctions a common 9-base-pair segment of HBV DNA, 5' C-A-C-C-T-C-T-G-C. The other two host-viral junctions mapped to the pre-S region and to the core region of the viral genome, showing no peculiar feature. These results show that HBV DNA can integrate via a specific viral DNA sequence.

Base Composition↗
PubMed1984

Detection of hepatitis B virus DNA in pancreas, kidney and skin of two human carriers of the virus.

Using the Southern blot technique, we have analysed the presence and state of hepatitis B virus (HBV) DNA in non-hepatic tissue from two human HBV carriers. HBV DNA sequences were detected in the pancreas, kidney and skin, demonstrating HBV infection of these organs. Moreover, the restriction DNA patterns were consistent with the integration of these viral sequences into high molecular weight DNA. These results demonstrate that HBV infection is not restricted to the liver.

Aged↗
PubMed1983

Characterization of integrated hepatitis B viral DNA cloned from a human hepatoma and the hepatoma-derived cell line PLC/PRF/5.

Recombinant phage clones carrying integrated hepatitis B virus (HBV) DNA sequences have been isolated from two phage libraries made from human DNA of a hepatoma and a hepatoma-derived cell line. One clone from each library has been characterized both by restriction mapping and by electron microscopy. In one clone there is at least one complete and uninterrupted HBV genome, and in the other the HBV sequences are composed of two major subgenomic fragments inverted with respect to each other. The host-virus junctions are localized within the positions 1,700-2,600 base pairs on the physical map of the free viral genome. The pre-S/S (surface antigen gene) region is conserved between the two clones. The two clones do not have common cellular sequences nor do they contain cellular homologues to six retroviral oncogenes. For one clone, the hepatitis B surface antigen gene was found to be functional when introduced into mouse thymidine kinase-negative cells by transfection.

Carcinoma, Hepatocellular↗