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Biomedical subjects

R Monier

Publications and source records attributed to R Monier.

At least 19 recordsLinked to original sources
PubMed1995

Activating mutations of the TSH receptor in differentiated thyroid carcinomas.

A series of 14 thyroid carcinomas, characterized for their basal adenyl cyclase activity (ACA), was examined for the presence of activating point mutations in the TSH receptor (TSHR) gene. Sequencing of the carboxyl-part of this gene revealed the presence of a somatic and heterozygotic point mutation in codon 623 in three out of six tumors showing a constitutively enhanced ACA and a poor response to TSH stimulation. The mutation determines the substitution of a serine for an alanine in the third intracellular loop of the receptor, in a region critical for signal transduction. One tumor bearing a TSHR mutation presented also a N-ras point mutation. Both mutations were detected also in a lung metastasis of this tumor. Our data represent the first report of alterations in the TSHR gene in thyroid malign neoplasia. TSHR mutations may indeed participate, as well as the G alpha s protein (gsp oncogene), in the oncogenesis of some differentiated thyroid carcinomas presenting increased basal levels of cAMP and a poor response to TSH.

Adenocarcinoma, Follicular↗
PubMed1995

Pattern of ras and gsp oncogene mutations in radiation-associated human thyroid tumors.

The preferential activation of the Ki-ras oncogene in follicular radiation-associated human thyroid carcinomas, has been suggested by Wright et al. (1991). However, only 12 thyroid tumors were analysed in this study. In order to confirm if radiation favours, in human thyroid tumorigenesis, the appearance of a particular molecular lesion, we studied 33 benign and malignant human radiation-associated thyroid tumors. We used polymerase chain reaction (PCR) amplification and allele-specific hybridization with mutant-specific probes for the three ras genes and the gsp oncogene. Compared to 85 'spontaneous' human thyroid tumors, the radiation-associated cases: (1) show a similar overall frequency of ras and gsp mutations (about 30% and 6% respectively); (2) present a similar frequency of mutation of the three ras genes without any predominance in adenomas and papillary carcinomas and (3) all Ki-ras mutations were found in papillary carcinomas (4/15). ras and gsp genes were never found mutated simultaneously, suggesting an alternative role for both oncogenes in the thyroid tumorigenic radiation-associated process.

Adenoma↗
PubMed1995

Genetic alterations in thyroid hyperfunctioning adenomas.

Thirty-seven thyroid autonomously hyperfunctioning adenomas were screened for mutations in the TSH receptor (TSHR), G alpha s (gsp), and ras genes. Polymerase chain reaction-amplified fragments of the TSHR C-terminal part (exon 10), the G alpha s (exons 8 and 9), and the three ras genes were obtained from the genomic DNA extracted from 37 tumors and their adjacent normal tissues and were studied by direct nucleotide sequencing and hybridization with synthetic probes. A point mutation in the third intracellular loop (codon 623) of the TSHR was found in 3 of 37 adenomas studied. This mutation codes for a change (Ala to Ser) in the TSHR structure and is somatic and heterozygotic. Constitutive activation of the TSHR was demonstrated by an increase in basal cAMP levels after transfection of Chinese hamster ovary cells with a mutated Ser623-TSHR complementary DNA. Nine gsp[00ae]MDRV[00af]- and one ras-activating mutations were also detected. No simultaneous alteration of the studied genes was present. Thus, in hyperfunctioning thyroid adenomas, our data suggest that a mutational activation of the TSHR and gsp genes may play a tumorigenic role through constitutive activation of the cAMP pathway.

Adenoma↗
PubMed1994

Oncogenic potential of guanine nucleotide stimulatory factor alpha subunit in thyroid glands of transgenic mice.

Transgenic mice have been used to address the issue of the oncogenic potential of mutant guanine nucleotide stimulatory factor (Gs) alpha subunit in the thyroid gland. The expression of the mutant Arg-201-->His Gs alpha subunit transgene has been directed to murine thyroid epithelial cells by bovine thyroglobulin promoter. The transgenic animals develop hyperfunctioning thyroid adenomas with increased intracellular cAMP levels and high uptake of [125I]iodine and produced elevated levels of circulating triiodothyronine and thyroxine. These animals demonstrate that the mutant form of Gs alpha subunit carries an oncogenic activity, thus supporting the model that deregulation of cAMP level alters growth control in thyroid epithelium. These animals represent models for humans with autonomously functioning thyroid nodules.

Animals↗
PubMed1992

Metastatic phenotype of murine tumor cells expressing different cooperating oncogenes.

Four murine cellular tumor models expressing various combinations of oncogenes (SV40 large T and v-Ha-ras, SV40 large T and v-src, SV40 large T and neu, adenovirus EIA and v-Ha-ras) induce sarcoma when they are inoculated s.c. into the DBA/2 syngenic mice. The metastatic patterns, distribution and fate of these tumor cells transplanted by two different routes into syngenic DBA/2 mice have been studied. All the tumor cell lines except EIA-ras, induce massive overt artificial metastases principally in the lung after i.v. injection. In s.c. tumor-bearing mice, a few resting cells colonize the lung as micrometastases. When removed from this tissue context and injected s.c. these cells regain their proliferative potential and grow as local tumors which again give rise to occult pulmonary micrometastases.

Adenovirus Early Proteins↗
PubMed1991

gsp mutations in human thyroid tumours.

The presence of gsp mutations at codons 201 and 227 in the gene coding for the alpha subunit of the GTP-binding Gs protein which stimulates adenylyl cyclase (AC) has been investigated in 31 samples of differentiated thyroid tumours, which had been previously characterized with respect to their adenylyl cyclase activity (ACA) before and after stimulation by thyroid-stimulating hormone (TSH). Polymerase chain reaction (PCR) amplification of DNA extracted from these tumours, followed by high stringency oligonucleotide probing, enabled the detection of mutations in three samples originating from tumours with high constitutive ACA, which was not significantly further stimulated by TSH. Two mutations were at codon 227 and replaced Gln227 by His or Lys, and one was at codon 201, with the substitution of Arg201 by Ser. Because thyrocytes belong to the subset of differentiated cells which are programmed to proliferate in response to elevated cAMP levels, the gsp mutations observed in some differentiated thyroid carcinomas probably contributed to their tumorigenic phenotype.

Adenocarcinoma↗
PubMed1991

[Conclusion and future prospects].

The genetic events which are associated with tumorigenesis concern two classes of genes: proto-oncogenes and anti-oncogenes. The first code for products which take part in the positive control of cellular proliferation; the second code for products which are involved in the negative regulation of cell growth. The identification of genes involved in the genetic predisposition to some cancers can be used in predictive medicine, while the observations on proto-oncogenes are already of prognostic value in some instances. In the future they will lead to new therapeutic approaches.

Cell Cycle↗
PubMed1990

Oncogenes and anti-oncogenes in tumorigenesis.

Recent advances have led to the identification of cellular genes which are involved in the initiation and progression of tumorigenesis. The proto-oncogenes, which normally participate in the regulation of cell proliferation and differentiation, can become oncogenes through alterations in the regulation of their expression and/or their coding sequences. Their contribution to the tumorigenic phenotype is dominant. The anti-oncogenes or tumor suppressor genes or recessive oncogenes are normally implicated in a negative regulation of cellular proliferation. The loss of their activity contributes to tumorigenesis in a recessive manner. Genetic events activating proto-oncogenes or inactivating anti-oncogenes accumulate in the same cell during tumor progression and co-operate to determine the malignant invasive phenotype of advanced tumors.

Cell Differentiation↗
PubMed1990

Presence of mutations in all three ras genes in human thyroid tumors.

Polymerase chain reaction (PCR) amplification followed by oligonucleotide probing was used to investigate the presence of ras genes mutations in human thyroid adenomas and carcinomas. The results confirm the frequent occurrence of mutations in all three ras genes in both adenomas and carcinomas, in agreement with the hypothesis that the ras mutations may constitute early steps in thyroid tumorigenesis. No evident correlation between the frequency of ras mutations, the identity of the mutated ras gene, the position affected in the ras gene or the type of mutation and the pathological features is apparent. However, definitive conclusion on this point is precluded because of the small number of tumors examined at the present time.

Adenoma↗
PubMed1988

Detection of activated ras oncogenes in human thyroid carcinomas.

Focus formation following DNA transfection of mouse 3T3-Vill cells was used to search for the presence of activated oncogenes in human thyroid tumors. Oncogenes belonging to the ras family were detected in four out of six thyroid carcinomas (Ki-ras in one anaplastic tumor and one follicular moderately differentiated tumor and Ha-ras and N-ras in two papillary tumors). Normal thyroid tissue samples obtained from two patients, one with an anaplastic tumor and one with a benign adenoma, and samples from 4 benign adenomas and from one toxic goiter of a patient with Graves' disease gave negative results. In one case, restriction enzyme analysis demonstrated the presence of a mutation in codon 12 of the activated Ha-ras oncogene. Our data show that all three ras proto-oncogenes can become activated in malignant thyroid tumors.

Adenoma↗
PubMed1986

Modulation of c-fos and c-myc mRNA levels in normal human lymphocytes by calcium ionophore A23187 and phorbol ester.

A transient expression of the proto-oncogenes c-fos and c-myc is rapidly induced by growth factors or mitogens in different cell types including lectin-stimulated lymphocytes. To elucidate the early events of lymphocyte activation, we determined (by Northern blot analysis) the steady-state levels of c-fos and c-myc mRNA in normal human peripheral blood lymphocytes (PBL) stimulated with the Ca2+ ionophore A23187 and/or 12-O-tetradecanoylphorbol-13-acetate (TPA), whose biological activities are well defined. We report that ionophore A23187 (0.5 microM) or, to a significantly lesser extent, TPA (0.5 ng/ml), neither of which is mitogenic alone at these concentrations, nevertheless can induce a transient accumulation of the proto-oncogene transcripts. These results indicate that a significant accumulation of c-fos and c-myc mRNA can occur without subsequent lymphocyte proliferation. The combination of these two mitogens increases the induced levels of both types of c-onc mRNAs. The level of mRNA accumulation correlates with the degree of proliferation induced by mitogenic combinations of ionophore A23187 and TPA, as measured by [3H]thymidine incorporation. Thus, these compounds act synergistically both with respect to c-fos and c-myc mRNA accumulation and to mitogenicity in human PBL. We also studied the level of c-fos transcripts following stimulation of the T lymphocyte T3/Ti receptor complex, using monoclonal anti-T3 antibodies. We observed that mitogenic doses of anti-T3 also induce an accumulation of c-fos mRNA, whose induction also is synergized by TPA. These results suggest that transient accumulation of c-fos; as well as c-myc, mRNA is a normal event of the immune response. They confirm that Ca2+ ionophore combined with TPA can mimic some molecular features of the early steps of normal human PBL activation.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1985

Increased level of amplification of the c-myc oncogene in tumors induced in nude mice by a human breast carcinoma cell line.

Cell line SW 613-S, derived from a human breast carcinoma, contained double minute chromosomes (DMs) but lost them progressively upon in vitro cultivation. These cells were tumorigenic in nude mice. Cell lines were derived from the tumors and were found to have a high DM content. In three such cell lines, DMs were stably maintained upon in vitro cultivation, whereas in another they were progressively lost. We found that the c-myc oncogene is amplified 5- to 10-fold in SW 613-S and 20- to 90-fold in the different cell lines derived from the tumors. At least part of the additional c-myc copies were found associated with a purified DM fraction. In cell lines which lost the DMs during in vitro passages, the level of amplification was maintained. In situ hybridization experiments indicated that this loss was compensated by the acquisition of copies of the c-myc gene integrated into a chromosome. No major rearrangement of the amplified c-myc gene was detected. The amount of c-myc messenger RNAs is roughly proportional to the level of amplification. Our results indicate that growth of SW 613-S cells as tumors in nude mice selected cells with an increased level of amplification and expression of the c-myc oncogene.

Animals↗
PubMed1982

Effect of tumor promoters on soft-agar growth of Swiss 3T3 cells infected with SV40 tsA mutants.

The availability of many SV40 mutants, in which the ability of the virus to transform fibroblasts is variously affected, has prompted us to investigate the effect of treating SV40-infected cells with known tumor promoters on the expression of the transformed phenotype. Using mouse Swiss 3T3 cells and various SV40 tsA mutants unable to transform these cells at 39 degrees C, we have observed a dramatic effect of the potent phorbol ester promoter, 12-O-tetradecanoyl-phorbol-13-acetate, on the formation of macroscopic colonies in soft-agar at the restrictive temperature of 39 degrees C. The efficiency of other phorbol esters and various substances such as anthralin, saccharin, sodium cyclamate, mellitin, griseofulvin and benzoyl peroxide, was in agreement with their reported promoting activities suggesting that mouse Swiss 3T3 cells infected with SV40 tsA mutants could provide a quick and easy test to detect promoters.

Agar↗
PubMed1982

Cell transformation by simian virus 40 mutants.

The role played by the early region of simian virus 40 (SV40) in cellular transformation has been investigated using a series of constructed double mutants which associated a d1-54-59 mutation with either a tsA mutation or a deletion located in the 3'-terminal part of the A gene. The ability of secondary mouse or rat embryo infected cells to clone at low cell density was used to select transformants, which were later tested for anchorage-independent growth. The results show that the conversion of a mouse or rat embryo cell into a continuous cell line requires the permanent expression of the A gene. SV40 mutants were also used in conjunction with tumor promoters to induce anchorage-independent growth of Swiss 3T3 cells. SV40-tsA-infected cells produced macrocolonies when plated in soft-agar at the restrictive temperature of 39 degrees C in the presence of the potent tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). At the permissive temperature of 33 degrees C, TPA increased the number of soft-agar clones about 4-fold. A good correlation between the formation of macrocolonies at 39 degrees C and the reported promoting activity of various compounds, including teleocidin B and anthralin, was observed. Saccharin behaved in this system as a weak promoter, since an effect is observed at concentrations around 1 X 10(-4) M, while the effect of TPA is clearly detected at 1.6 X 10(-10) M. The results suggest that SV40-tsA-infected Swiss 3T3 cells might provide a quick and easy test for tumor promoters.

Animals↗
PubMed1981

Mapping of the viral mRNA encoding a super-T antigen of 115,000 daltons expressed in simian virus 40-transformed rat cell lines.

Simian virus 40-transformed V11 F1 clone 1 subclone 7 rat cells produced a considerable amount of an elongated form of large-T antigen with an Mr of 115,000 (115K super-T antigen), but these cells did not produce detectable traces of normal-sized large-T antigen (86,000 daltons) (P. May, M. Kress, M. Lange, and E. May, Cold Spring Harbor Symp. Quant. Biol. 44:189-200, 1980). First, a comparison of the tryptic peptide fingerprints of 115K super-T and large-T antigens suggested that 115K super-T antigen is simian virus 40 coded and contains a duplication of amino acid sequences of large-T antigen. Second, from S1 mapping analysis of 115K super-T mRNA, performed with various restriction fragments of simian virus 40 DNA, it was concluded that super-T mRNA is a form of large-T mRNA containing a tandem duplication of the sequence extending from approximately 0.46 to 0.35 map unit. The duplicated sequence corresponded to that region of the simian virus 40 genome in which 12 of 13 tsA mutation sites are clustered (C. J. Lai and D. Nathans, Virology 66:70-81, 1975).

Animals↗