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M P Simon

Publications and source records attributed to M P Simon.

At least 19 recordsLinked to original sources
PubMed2001

Structural and functional analysis of a chimeric protein COL1A1-PDGFB generated by the translocation t(17;22)(q22;q13.1) in Dermatofibrosarcoma protuberans (DP).

Dermatofibrosarcoma protuberans (DP), an infiltrative skin tumour of intermediate malignancy, presents specific cytogenetic features such as reciprocal translocations t(17;22)(q22;q13.1) or supernumerary ring chromosomes derived from t(17;22). We have previously shown that both rings and translocated chromosomes derived from t(17;22) presented the same molecular rearrangement with fusion of the COL1A1 gene on chromosome 17 to the PDGFB gene on chromosome 22. To study the structure and function of the COL1A1-PDGFB chimeric protein, we used a tumour-derived chimeric COL1A1-PDGFB cDNA to perform stable and transient transfections in the Chinese hamster lung fibroblastic cell line PS200 and the human epithelial cell line HEK293. We demonstrated that the stably transfected clones that expressed the COL1A1-PDGFB chimeric protein became growth factors independent and tumorigenic in nude mice. In addition, COL1A1-PDGFB transfected cell supernatants significantly stimulated fibroblastic cell growth, through the activation of the PDGFB receptor pathway. By using anti-PDGFB and specific anti-COL1A1-PDGFB antibodies, we showed that, similar to PDGFB, the COL1A1-PDGFB chimeric proteins are processed in transfected cells into mature PDGFB dimers. These results strongly suggest that the COL1A1-PDGFB chimeric gene expression associated with DP, induces tumours formation through production of mature PDGFB, in an autocrine or paracrine way. Strikingly, mutagenesis experiments indicated that uncleaved COL1A1-PDGFB forms are mitogenic and therefore could contribute, as well as mature PDGFB, to the establishment of a transformed phenotype.

Animals↗
PubMed1998

COL1A1-PDGFB fusion in a ring chromosome 4 found in a dermatofibrosarcoma protuberans.

Dermatofibrosarcoma protuberans (DP), an infiltrative skin tumor of intermediate malignancy, presents specific cytogenetic features such as reciprocal translocations t(17;22)(q22;q13.1) or, more often, supernumerary ring chromosomes derived from t(17;22). Different translocations, including t(2;17) and t(X;7), have also been described. We have shown previously that both r(17;22) and t(17;22) present the same molecular rearrangement fusing the COL1A1 gene on chromosome 17 and the PDGFB gene on chromosome 22. Out of our series of 16 DPs, we detected an extra ring chromosome in tumor T96-1175, which juxtaposed sequences from chromosomes 4 and 17. As shown by fluorescence in situ hybridization (FISH) using chromosome painting and alpha-satellite probes, T96-1175 apparently lacked chromosome 22 material in the ring. However, involvement of chromosome 22 through a rearrangement of PDGFB was shown by Southern blotting, reverse transcriptase-polymerase chain reaction (RT-PCR), and FISH. This study demonstrates that a cryptic molecular rearrangement between chromosomes 17 and 22 occurred in addition to the recombination of chromosomes 4 and 17 initially identified by FISH. Assessment for cryptic molecular events should be performed in other variant DP rearrangements.

Adult↗
PubMed1997

Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma.

Dermatofibrosarcoma protuberans (DP), an infiltrative skin tumour of intermediate malignancy, presents specific features such as reciprocal translocations t(17;22)(q22;q13) and supernumerary ring chromosomes derived from the t(17;22). In this report, the breakpoints from translocations and rings in DP and its juvenile form, giant cell fibroblastoma (GCF), were characterised on the genomic and RNA level. These rearrangements fuse the platelet-derived growth factor B-chain (PDGFB, c-sis proto-oncogene) and the collagen type I alpha 1 (COL1A1) genes. PDGFB has transforming activity and is a potent mitogen for a number of cell types, but its role in oncogenic processes is not fully understood. COL1A1 is a major constituent of the connective tissue matrix. Neither PDGFB nor COL1A1 have so far been implicated in any tumour translocations. These gene fusions delete exon 1 of PDGFB, and release this growth factor from its normal regulation.

Chromosome Breakage↗
PubMed1996

Another case of t(17;22)(q22;q13) in an infantile dermatofibrosarcoma protuberans.

We have identified a new dermatofibrosarcoma protuberans (DP) case with a t(17;22) (q22;q13) occurring in a child. The translocation was substantiated by the presence of one or two copies of the sole der(22)t(17;22). This rearrangement added to two normal chromosomes 17 and one or two chromosomes 22, resulted in trisomy 22cen-q13 and trisomy (or tetrasomy) 17q22-25. This observation confirms the specificity of the association of DP with the t(17;22) found together with extra copies of the der(22)t(17;22). It also points out a possible prevalence of translocation rather than rings in DP of the childhood disease.

Antigens, CD34↗
PubMed1996

Translocation, t(17;22)(q22;q13), in dermatofibrosarcoma protuberans: a new tumor-associated chromosome rearrangement.

A translocation, t(17;22)(q22;q13), was identified in two cases of dermatofibrosarcoma protuberans (DP). They bring to four the number of DP cases characterized by an identical t(17;22)(q22;q13), which can be considered as a new tumor-associated chromosome rearrangement. To date, this translocation has been found only in DP and its juvenile form, giant-cell fibroblastoma. This finding has two major consequences. First, it casts light on the development and significance in DP of ring chromosomes which consistently harbor sequences derived from chromosomes 17 and 22. Second, the identification of this new chromosome marker, and eventually of the underlying molecular rearrangement, should help to classify DP, a soft-tissue tumor of still uncertain cell origin. In addition, it could be used to differentiate DP from truly benign or malignant entities, in order that this tumor of intermediate malignancy could be adequately managed.

Adolescent↗
PubMed1995

Ring 22 chromosomes in dermatofibrosarcoma protuberans are low-level amplifiers of chromosome 17 and 22 sequences.

Ring chromosomes have been found with some regularity as solid tumors have come increasingly under cytogenetic study. The full genetic content and significance of these rings remain unclear. Dermatofibrosarcoma protuberans, a tumor of the deep dermis, consistently has supernumerary ring chromosomes, sometimes as the sole detectable cytogenetic change. Using a modified method for comparative genomic hybridization and fluorescent in situ hybridization with a panel of various probes, we found that these ring chromosomes consistently contain the chromosome 22 centromere along with interstitial sequences from chromosomes 17 and 22, specifically from regions 17q23-24 and 22q11-12. The ring chromosomes in dermatofibrosarcoma protuberans are vehicles for a particular pattern of relatively low-level genomic amplification of selected sequences.

Adult↗
PubMed1993

Expanded range of 11q13 breakpoints with differing patterns of cyclin D1 expression in B-cell malignancies.

We have analyzed the BCL1 locus in a series of 24 B-cell tumors and cell lines with rearrangements of 11q13 (mostly t(11;14)(q13;q32) translocations). Using Southern hybridization and/or fluorescence in situ hybridization (FISH) on metaphase chromosomes, we have not only confirmed the scattering of the breakpoints between the BCL1 locus and the cyclin D1 gene (CCND1), but also shown that some of the breakpoints could be as far as 500 kb on either side of the latter. Expression of CCND1 was not restricted to cases with t(11;14)(q13;q32), but was also associated with other 11q13 rearrangements, such as a t(8;11)(p22;q13). Whatever the alteration at 11q13, a correlation was observed between the expression of CCND1 and the presence of a breakpoint within 150 kb upstream of the gene. On the contrary, three samples, including a bona fide t(11;14) translocation and two cases with breakpoints located outside the BCL1-CCND1 area, did not exhibit detectable levels of CCND1 transcripts. Our results raise the possibility that several discrete molecular events can take place at 11q13 in B-cell malignancies.

Base Sequence↗
PubMed1992

Localization of 11q13 loci with respect to regional chromosomal breakpoints.

We have employed two strategies to map 13 markers located at 11q13. First, we used pulsed-field gel electrophoresis of DNA fragments obtained with methylation-sensitive restriction enzymes. The markers used in this study were scattered over 8.4 Mb and, for most of them, could not be linked one to another. A second mapping strategy employed hybridization to either DNA of somatic hybrids containing various parts of the long arm of chromosome 11 or metaphase chromosomes of a B-cell line containing the t(11;14)(q13;q32) translocation. We were able to sort out the centromeric from the telomeric probes with respect to translocation breakpoints taken as reference chromosomal landmarks by this approach. BCL1, which corresponds to the region where the t(11;14)(q13;q32) translocation breakpoints are clustered, appears as a boundary between two areas of human/mouse homology present in conserved syntenic regions on mouse chromosomes 7 and 19.

Animals↗
PubMed1990

Molecular genetics of human bladder carcinomas.

Bladder cancer corresponds to a tumor type whose clinical behavior is difficult to predict. A better understanding of this pathology is expected from molecular genetics, which brings together cytogenetics and molecular biology. Therefore, we have tried to overview correlations between chromosome abnormalities and the presence, in the vicinity of the altered loci, of genes (oncogenes and others) that could be involved in bladder oncogenesis and/or tumor progression. In addition to oncogene activation by point mutations, gene amplification, or deregulation of gene expression, several cytogenetic as well as molecular evidences point to genetic deletions (existence of "tumor suppressor genes") being involved in those processes.

Carcinoma in Situ↗
PubMed1990

BCL-1 participates in the 11q13 amplification found in breast cancer.

In an attempt to probe the significance of HST and INT-2 gene amplification in human breast carcinomas, we have surveyed the amplification status of five molecular markers located on the long arm of chromosome 11 (BCL-1, HST, INT-2 & SEA on 11q13, and ETS-1 on 11q23) in a population of 297 mammary tumors. ETS-1 was rarely amplified and always independently from the other proto-oncogenes. Concerning band q13: (i) 50 tumors (approximately 17%) were co-amplified for BCL-1, HST & INT-2; (ii) in 3 cases, amplification extended to the SEA gene; (iii) in 6 carcinomas, BCL-1 was the only amplified marker. The fact that we never observed amplification of HST & INT-2 independently of BCL-1, which in turn can be amplified solely, suggests the presence, between HST/INT-2 and BCL-1, of a genetic element which could be important in the development of a subset of mammary tumors.

Breast Neoplasms↗
PubMed1989

Proto-oncogene amplification and human breast tumor phenotype.

Amplification of c-myc, c-erbB-2, hst and int-2 proto-oncogenes was investigated in two independently collected breast tumor series comprising 292 carcinomas. Differences in the frequencies of amplification could be observed between these two series for c-myc (9.3% vs. 20.8%) and hst/int-2 (21.5% vs. 15.6%) whereas similar values were found for c-erbB-2 (22.5% vs. 20.3%). Statistical correlations between amplification and disease parameters were also dependent on population sampling. Therefore we performed our statistical analysis on the pooled populations and focused on the 219 primary breast carcinomas from patients without therapy prior to surgery. Amplification of c-erbB-2 was strongly correlated to the absence of either estrogen (ER-, P = 0.003) or progesterone (PR-, P = 0.004) receptors. An amplified c-myc was significantly associated with PR- (P = 0.005) and was prevalent in high grade tumors. On the contrary, hst/int-2 amplification was correlated to PR+ tumors (P = 0.01) and was more frequent in ER+ and low grade tumors, and was also correlated with lymph node involvement (P = 0.04). Our data suggest that amplification of each of these proto-oncogenes could be representative of a particular subset of breast tumors. Therefore, proto-oncogene amplification may be helpful in characterizing new biological subclasses in human breast cancer.

Breast Neoplasms↗
PubMed1987

Expression of c-myc is under dietary control in rat liver.

Expression of c-myc has often been related to the control of growth and differentiation of a variety of cell types. However, in some cases, such a relation has not been found. The rate of cell division is very low in liver, but c-myc expression is yet easily detected. We show here that a short-time physiological fasting results in a dramatic decrease of c-myc expression in rat liver. This effect does not seem to be dependent on glucagon, since administration of glucagon leads to an increase in c-myc mRNA. This is to our knowledge, the first evidence of a physiological variation of proto-oncogene expression linked to food intake, and we suggest that this variation could play a role in liver cell growth control.

Animals↗
PubMed1986

Tissue-specific heterogeneity of the 3'-untranslated region of L-type pyruvate kinase mRNAs.

A single L-type pyruvate kinase (PK) gene seems to exist per haploid genome. It is expressed in the liver, kidney and small intestine in the form of three mRNA species of 2, 2.2 and 3.2 X 10(3) bases (kb). All three species are polyadenylated and translatable into the same L-type subunit. Primer extension experiments demonstrate that all three PK mRNAs have the same 5' ends. Nuclease S1 protection experiments with various cDNA and 3' genomic probes indicate that the different mRNA species only differ by the length of their 3' noncoding region. The mechanism responsible for the production of the three transcripts seems to be the use of alternative unusual polyadenylation sites. Run-on assays with specific probes recognizing only the 3.2-kb or all three mRNA species show that the transcription proceeds across the gene with similar rate. This means that the process involved in generation of the three transcripts is a posttranscriptional event, probably due to different sites of endonucleolytic cleavage of primary transcripts extending 3' from the gene region encoding the mature mRNAs. The ratio between the different PK mRNA species is, to a certain extent, tissue-specific and changes with development. The role of an 'identifier sequence' located in the 3' noncoding sequence of the 3.2-kb species in such a tissue-specific use of alternative polyadenylation sites is discussed.

Animals↗
PubMed1986

Sequences complementary to the brain-specific "identifier" sequences exist in L-type pyruvate kinase mRNA (a liver-specific messenger) and in transcripts especially abundant in muscle.

A sequence complementary to the brain-specific identifier sequence has been found in the 3' untranslated extension of the heavy 3.2-kilobase (kb) long liver L-type pyruvate kinase mRNA while it is absent in the other two 2- and 2.2-kb long pyruvate kinase mRNA species. A 53-base fragment corresponding to this identifier sequence was subcloned in both orientations in the single-stranded bacteriophage M13, both strands being used as probes to detect homologous sequence in different tissues. Both strands are transcribed in various tissues and are detected in heterogeneous high molecular weight RNA species which are especially abundant in the adult muscle. In addition, the probe identical to the identifier sequence recognized a discrete 0.6-kb RNA species in the muscle and the probe complementary to the identifier-sequence recognized the expected two small brain-specific identifier BC-1 and BC-2 RNAs described by Sutcliffe et al. (Sutcliffe, J. G., Milner, R. J., Bloom, F. E., and Lerner, R. A. (1982) Proc. Natl. Acad. Sci. U. S. A. 79, 4942-4946; Sutcliffe, J. G., Milner, R. J., Gottesfeld, J. M., and Lerner, R. A. (1984) Nature 308, 237-241; Milner, R. J., Bloom, F. E., Lai, C., Lerner, R. A., and Sutcliffe, J. G. (1984) Proc. Natl. Acad. Sci. U. S. A. 81, 713-717; Sutcliffe, J. G., Milner, R. J., Gottesfeld, J. M., and Reynolds, W. (1984) Science 225, 1308-1314).

Animals↗
PubMed1986

Complete nucleotide and deduced amino acid sequences of rat L-type pyruvate kinase.

Four overlapping cDNA clones for L-type pyruvate kinase (PK-L) were isolated from carbohydrate-induced rat liver cDNA libraries. They contained all the coding sequence of the enzyme from the 7th codon and the entire 3'-untranslated extension up to the poly(A) tail. The sequence of the first 7 codons and that of the 5'-untranslated region were determined by primer extension. The analyzed PK-L mRNA has 19 5'-untranslated bases, 1629 coding bases and 1281 3'-untranslated bases without the poly(A) tail; it corresponds to the heavier, 3.2 kb species of the L-type mRNAs. The codons for the phosphorylatable site are located at the 5'-end of the messenger. The unusually long 3'-untranslated extension contains a repetitive element complementary to the 'brain-specific' identifier sequence described by Sutcliffe et al. [(1982) Proc. Natl. Acad. Sci. USA 79, 4942-4946].

Amino Acid Sequence↗
PubMed1985

Characterization and metabolic regulation of a liver-specific 5.4-kilobase mRNA whose synthesis is transcriptionally induced by carbohydrates and repressed by glucagon and cyclic AMP.

Four clones derived from a carbohydrate-induced rat liver cDNA library were found to hybridize with a 5.4-kilobase mRNA species encoding a 36 kDa protein. This mRNA was abundant in the liver, barely detectable in adipocytes and kidney, and absent from the other tissues tested. In the liver, the mRNA was fully induced by a carbohydrate-rich diet, but was undetectable during both starvation and feeding with a protein-rich or lipid-rich diet. Adrenalectomized, thyroidectomized and diabetic animals did not express the mRNA in their liver when re-fed with the carbohydrate-rich diet. When these animals were given the missing hormone, the amount of hybridizable RNA returned to normal values, but administration of the hormone alone failed to induce mRNA synthesis in starved animals. Both glucagon and its second messenger, cyclic AMP, abolished the induction of the mRNA in re-fed animals. Exogenous insulin, whatever the dose, did not reverse the inhibitory action of glucagon. In an isolated nuclei transcription system, no detectable RNA transcripts were found in starved animals, whereas feeding the animals with the carbohydrate-rich diet led to a maximum rate of gene transcription. Although unidentified, this mRNA proves to be a remarkable marker of dietary and hormonal control of gene expression in vivo. It will provide a useful model for further analysis of the role of cyclic AMP in regulating the transcription of eukaryotic genes.

Animals↗