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See detailIn Silico Dynamic Molecular Interaction Networks for the Discovery of New Therapeutic Targets
Vujasinovic, Todor; Zampera, André Sinisa; Jackers, Pascale ULg et al

in Current Pharmaceutical Design (2010), 16(20), 2241-2251

Systems biology has emerged as a major trend in biological research during the past decade. As living organisms are described in more and more detail, it aims at filling the gap between understanding ... [more ▼]

Systems biology has emerged as a major trend in biological research during the past decade. As living organisms are described in more and more detail, it aims at filling the gap between understanding basic molecular processes and complex biological systems in which new properties often emerge from the combination of these elementary processes. This approach culminates in the development of computer-based mathematical models of physiological and pathophysiological processes. We review the state of the art in dynamic modelling, with emphasis on two complementary approaches: the modelling of small systems that is mostly developed by academic teams and aims at understanding generic biological properties, and the modelling of large systems that is mostly implemented by industrial companies and aims at the generation of new therapeutic strategies. We also provide an example of such large-scale modelling applied to the identification of drug targets for neurodegeneration. [less ▲]

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See detailMCF-7/BOS cells membrane proteome: comparison of two isolation methods using mass spectrometry
Bertrand, Virginie ULg; Massart, Anne-Cécile ULg; De Pauw, Marie-Claire ULg et al

Poster (2009)

Membrane proteins play an important role in biological processes but their isolation and quantification using classical techniques is often limited due to their poor solubility and relatively low ... [more ▼]

Membrane proteins play an important role in biological processes but their isolation and quantification using classical techniques is often limited due to their poor solubility and relatively low abundance. These membrane markers have to be accessible to antibodies and should be potential therapeutic targets. The tests were conducted on MCF-7 / BOS cell line, immortal and easier to cultivate. The goal of this work is to obtain a pure membrane fraction to facilitate the analysis of the sample. To isolate transmembrane proteins, we compared two methods. The first one used different extraction cycles characterized by different buffers to isolate membrane proteins. The second method labelled accessible extracellular domains at the surface of MCF-7 cells with biotin prior to differential centrifugation. [less ▲]

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See detailMCF-7/BOS cells membrane proteome: comparison of two isolation methods using mass spectrometry
Bertrand, Virginie ULg; Massart, Anne-Cécile ULg; De Pauw, Marie-Claire ULg et al

Poster (2009)

Membrane proteins (MP) play an important role in biological processes. Isolation and quantification of these MP using classical techniques is often limited due to their poor solubility and relatively low ... [more ▼]

Membrane proteins (MP) play an important role in biological processes. Isolation and quantification of these MP using classical techniques is often limited due to their poor solubility and relatively low abundance. These membrane proteins enclosed markers which could be potential therapeutic targets. These potential therapeutic targets have to be accessible to antibodies and need to be presented in the plasmic membrane. Assays were conducted on MCF-7 / BOS cell line, immortal and easier to cultivate. The goal of this work is to obtain an enriched membrane fraction to facilitate the analysis of the sample and to simplify the complex proteins mixture. To isolate transmembrane proteins, we compared two methods. The first one used different extraction cycles characterized by different buffers to isolate membrane proteins. The second method labelled accessible extracellular domains at the surface of MCF-7 cells with biotin prior to differential centrifugation. The obtained enriched membrane proteome was digested with trypsin and/or Lysyl Endopeptidase. Obtained peptides were separated by 2D-HPLC chromatography and on-line analysed ion trap mass spectrometer, the Esquire HCT. [less ▲]

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See detailDeveloping predictive dynamic models of complex intracellular networks for neurological disease
Vafiadaki, Elizabeth; Depaulis, Antoine; Jackers, Pascale ULg et al

in FEBS Journal (2008), 275(Suppl. 1), 99-437

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See detailVALAPODYN: Validated Predictive Dynamic Model of Complex Intracellular Pathways Related to Cell Death and Survival
Depaulis, Antoine; Vafiadaki, Elizabeth; Jackers, Pascale ULg et al

in European Journal of Human Genetics (2007), 15(Suppl. 1),

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See detailDistal ERBB2 promoter fragment displays specific transcriptional and nuclear binding activities in ERBB2 overexpressing breast cancer cells
Delacroix, Laurence ULg; Begon, Dominique ULg; Chatel, Guillaume et al

in DNA & Cell Biology (2005), 24(9), 582-594

Overexpression of the ERBB2 gene occurs in 30% of human breast cancers and is correlated with poor prognosis. The deregulation is the consequence of an increased transcription level and gene amplification ... [more ▼]

Overexpression of the ERBB2 gene occurs in 30% of human breast cancers and is correlated with poor prognosis. The deregulation is the consequence of an increased transcription level and gene amplification. Several laboratories, including our own, have identified, in the proximal promoter, enhancers implicated in the gene overexpression. However, our previous studies of a 6-kb ERBB2 promoter fragment revealed the presence of repressing fragments, which were able to overcome the effect of the proximal enhancers. These repressing elements were functional in all cell lines, regardless of their endogenous ERBB2 expression level. Here, we show that a distal ERBB2 promoter region restores high transcription rates specifically in ERBB2 overexpressing breast cancer cells. This distal promoter region thus contains enhancers essential for the overexpression of the gene. By EMSA, performed with nuclear extract of cells overexpressing (BT-474) or not (MDA-MB-231) the ERBB2 gene, we show that at least two sequences of the distal promoter region are bound exclusively by BT-474 extract. Further experiments reveal that AP-2 transcription factors contribute to this differential binding activity, by binding recognition sequences located 4500 bp and 4000 bp upstream of the transcription start site. These sites are occupied by AP2 in vivo, as demonstrated by ChIP assay. Inactivation of AP-2 proteins in ERBB2 overexpressing cells reduces the distal promoter activity up to 70%, indicating the AP-2 factors are implicated in the strong distal enhancing effect. Moreover, we identified a 54-bp fragment that is bound specifically by BT-474 nuclear extract. Further experiments did not lead to the identification of the protein responsible for this binding. Our results thus highlight the importance of ERBB2 distal promoter region and further implicate AP-2 in ERBB2 overexpression in breast cancer cells. [less ▲]

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See detailYin Yang 1 cooperates with activator protein 2 to stimulate ERBB2 gene expression in mammary cancer cells.
Begon, Dominique ULg; Delacroix, Laurence ULg; Vernimmen, Douglas et al

in Journal of Biological Chemistry (2005), 280(26), 24428-34

Overexpression of the ERBB2 oncogene is observed in about 30% of breast cancers and is generally correlated with a poor prognosis. Previous results from our and other laboratories indicated that elevated ... [more ▼]

Overexpression of the ERBB2 oncogene is observed in about 30% of breast cancers and is generally correlated with a poor prognosis. Previous results from our and other laboratories indicated that elevated transcriptional activity contributes significantly to the overexpression of ERBB2 mRNA in mammary adenocarcinoma cell lines. Activator protein 2 (AP-2) transcription factors account for this overexpression through two recognition sequences located 215 and 500 bp upstream from the transcription start site. Furthermore, AP-2 transcription factors are highly expressed in cancer cell lines overexpressing ERBB2. In this report, we examined the cooperative effect of Yin Yang 1 (YY1) on AP-2-induced activation of ERBB2 promoter activity. We detected high levels of YY1 transcription factor in mammary cancer cell lines. Notably, we showed that YY1 enhances AP-2alpha transcriptional activation of the ERBB2 promoter through an AP-2 site both in HepG2 and in HCT116 cells, whereas a carboxyl-terminal-truncated form of YY1 cannot. Moreover, we demonstrated the interaction between endogenous AP-2 and YY1 factors in the BT-474 mammary adenocarcinoma cell line. In addition, inhibition of endogenous YY1 protein by an antisense decreased the transcription of an AP-2-responsive ERBB2 reporter plasmid in BT-474 breast cancer cells. Finally, we detected in vivo AP-2 and YY1 occupancy of the ERBB2 proximal promoter in chromatin immunoprecipitation assays. Our data thus provide evidence that YY1 cooperates with AP-2 to stimulate ERBB2 promoter activity through the AP-2 binding sites. [less ▲]

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See detailMechanisms responsible for ERBB2 gene overexpression in human breast and non-breast cancer cells. The role of AP-2 transcription factors - Review Article
Delacroix, Laurence; Vernimmen, Douglas; Begon, Dominique et al

in Cancer Therapy (2005), 3(issue B), 365-378

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See detailEts-dependent regulation of target gene expression during megakaryopoiesis
Jackers, Pascale ULg; Szalai, Gabor; Moussa, Omar et al

in Journal of Biological Chemistry (2004), 279(50), 52183-52190

Megakaryopoiesis is the process by which hematopoietic stem cells in the bone marrow differentiate into mature megakaryocytes. The expression of megakaryocytic genes during megakaryopoiesis is controlled ... [more ▼]

Megakaryopoiesis is the process by which hematopoietic stem cells in the bone marrow differentiate into mature megakaryocytes. The expression of megakaryocytic genes during megakaryopoiesis is controlled by specific transcription factors. Fli-1 and GATA-1 transcription factors are required for development of megakaryocytes and promoter analysis has defined in vitro functional binding sites for these factors in several megakaryocytic genes, including GPIIb, GPIX, and C-MPL. Herein, we utilize chromatin immunoprecipitation to examine the presence of Ets-1, Fli-1, and GATA-1 on these promoters in vivo. Fli-1 and Ets-1 occupy the promoters of GPIIb, GPIX, and C-MPL genes in both Meg-01 and CMK11-5 cells. Whereas GPIIb is expressed in both Meg-01 and CMK11-5 cells, GPIX and C-MPL are only expressed in the more differentiated CMK11-5 cells. Thus, in vivo occupancy by an Ets factor is not sufficient to promote transcription of some megakaryocytic genes. GATA-1 and Fli-1 are both expressed in CMK11-5 cells and co-occupy the GPIX and C-MPL promoters. Transcription of all three megakaryocytic genes is correlated with the presence of acetylated histone H3 and phosphorylated RNA polymerase II on their promoters. We also show that exogenous expression of GATA-1 in Meg-01 cells leads to the expression of endogenous c-mpl and gpIX mRNA. Whereas GPIIb, GPIX, and C-MPL are direct target genes for Fli-1, both Fli-1 and GATA-1 are required for formation of an active transcriptional complex on the C-MPL and GPIX promoters in vivo. In contrast, GPIIb expression appears to be independent of GATA-1 in Meg-01 cells. [less ▲]

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See detailFli-1 inhibits collagen type I production in dermal fibroblasts via an Sp1-dependent pathway.
Czuwara-Ladykowska, Joanna; Shirasaki, Fumiaki; Jackers, Pascale ULg et al

in Journal of Biological Chemistry (2001), 276(24), 20839-20848

Fibrosis is characterized by the excessive deposition of extracellular matrix (ECM), especially collagen. Because Ets factors are implicated in physiological and pathological ECM remodeling, the aim of ... [more ▼]

Fibrosis is characterized by the excessive deposition of extracellular matrix (ECM), especially collagen. Because Ets factors are implicated in physiological and pathological ECM remodeling, the aim of this study was to investigate the role of Ets factors in collagen production. We demonstrate that the expression of collagenous proteins and collagen alpha2(I) (COL1A2) mRNA was inhibited following stable transfection of Fli-1 in dermal fibroblasts. Subsequent analysis of the COL1A2 promoter identified a critical Ets binding site that mediates Fli-1 inhibition. In contrast, Ets-1 stimulates COL1A2 promoter activity. In vitro binding assays demonstrate that both Fli-1 and Ets-1 form DNA-protein complexes with sequences present in COL1A2 promoter. Furthermore, Fli-1 binding to the COL1A2 is enhanced via Sp1-dependent interaction. Studies using Fli-1 dominant interference and DNA binding mutants indicate that Fli-1 inhibition is mediated by both direct (DNA binding) and indirect (via protein-protein interaction) mechanisms and that Sp1 is an important mediator of the Fli-1 function. Furthermore, experiments using the Gal4 system in the context of different cell types as well as experiments with the COL1A2 promoter in different cell lines demonstrate that the direction and magnitude of the effect of Fli-1 is promoter- and cell context-specific. We propose that Fli-1 inhibits COL1A2 promoter activity by competition with Ets-1. In addition, we postulate that another factor (co-repressor) may be required for maximal inhibition after recruitment to the Fli-1-Sp1 complex. We conclude that the ratio of Fli-1 to Ets-1 and the presence of co-regulatory proteins ultimately control ECM production in fibroblasts. [less ▲]

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See detailHemorrhage, impaired hematopoiesis, and lethality in mouse embryos carrying a targeted disruption of the Fli1 transcription factor.
Spyropoulos, Demetri D.; Pharr, Pamela N.; Lavenburg, Kim R. et al

in Molecular & Cellular Biology (2000), 20(15), 5643-5652

The Ets family of transcription factors have been suggested to function as key regulators of hematopoeisis. Here we describe aberrant hematopoeisis and hemorrhaging in mouse embryos homozygous for a ... [more ▼]

The Ets family of transcription factors have been suggested to function as key regulators of hematopoeisis. Here we describe aberrant hematopoeisis and hemorrhaging in mouse embryos homozygous for a targeted disruption in the Ets family member, Fli1. Mutant embryos are found to hemorrhage from the dorsal aorta to the lumen of the neural tube and ventricles of the brain (hematorrhachis) on embryonic day 11.0 (E11.0) and are dead by E12.5. Histological examinations and in situ hybridization reveal disorganization of columnar epithelium and the presence of hematomas within the neuroepithelium and disruption of the basement membrane lying between this and mesenchymal tissues, both of which express Fli1 at the time of hemorrhaging. Livers from mutant embryos contain few pronormoblasts and basophilic normoblasts and have drastically reduced numbers of colony forming cells. These defects occur with complete penetrance of phenotype regardless of the genetic background (inbred B6, hybrid 129/B6, or outbred CD1) or the targeted embryonic stem cell line used for the generation of knockout lines. Taken together, these results provide in vivo evidence for the role of Fli1 in the regulation of hematopoiesis and hemostasis. [less ▲]

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See detailTnf-Alpha and Ifn-Gamma Down-Regulate the Expression of the Metastasis-Associated Bi-Functional 37lrp/P40 Gene and Protein in Transformed Keratinocytes
Clausse, Nathalie; van den Brûle, Frédéric; Delvenne, Philippe ULg et al

in Biochemical and Biophysical Research Communications (1998), 251(2), 564-9

The 37 LRP/p40 molecule is a bi-functional protein in which expression is increased in a large variety of cancers in association with their metastatic phenotype. Here we present the first data concerning ... [more ▼]

The 37 LRP/p40 molecule is a bi-functional protein in which expression is increased in a large variety of cancers in association with their metastatic phenotype. Here we present the first data concerning the 37 LRP/p40 gene promoter activity and show that it is very active in a cervix carcinoma cell line. Interestingly, despite hallmarks of a housekeeping gene, we show that the 37 LRP/p40 gene promoter can be down-regulated by two potentially anticancerous cytokines, TNF-alpha and IFN-gamma. In addition, the dual fate of the protein, i.e., being intracellularly involved in the cell translation machinery and incorporated into a 67-kDa cell surface protein functioning as a laminin receptor (67LR), is differentially affected by the treatment. Our data suggest multiple regulation levels in the control of the 67LR/37LRP/p40 molecule expression and uncover new clues for the understanding of both the control of expression of this metastasis-associated molecule and the IFN-gamma and TNF-alpha anticancerous action. [less ▲]

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See detailDifferential expression of galectin-1 and galectin-3 during first trimester human embryogenesis.
van den Brûle, Frédéric; Fernandez, Pedro L.; Buicu, Crina et al

in Developmental Dynamics : An Official Publication of the American Association of Anatomists (1997), 209(4), 399-405

Development of complex organisms requires specific temporospatial differentiation and expression of the correct phenotype through activation of a variety of genes. Galectins are mammalian lectins able to ... [more ▼]

Development of complex organisms requires specific temporospatial differentiation and expression of the correct phenotype through activation of a variety of genes. Galectins are mammalian lectins able to interact with various extracellular matrix glycoconjugates and have been implicated in several biological events including cell attachment, differentiation, apoptosis, embryogenesis, and cancer invasion and metastasis. In this study, we have examined the expression of galectin-1 and galectin-3 during human first trimester embryogenesis using immunohistochemistry and Western blotting. Variable amounts of galectin-1 and galectin-3 were detected in all tissue protein extracts. Galectin-1 expression was demonstrated in the connective tissue and derived tissues such as smooth and striated muscle cells, and in some epithelia, such as in the basal layers of the skin after 14 weeks and in the epithelial cells of the gonads. Galectin-3 was detected mainly in epithelia, such as the skin, epithelial lining of the digestive and respiratory tract, and urothelium and excretory tubes of the kidney, but also in the myocardial cells, in the peripheral and preossifying hypertrophic chondrocytes, and in the notochord and in the liver. Our study constitutes the first demonstration of galectin-1 and galectin-3 during human embryogenesis. The differential expression of these two lectins suggests that they could participate in the complex processes of tissue differentiation. [less ▲]

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See detailThe 37 LRP/P40 polypeptide: a multifunctional pleiotropic molecule involved in tumorigenesis and metastasis - A review
Clausse, Nathalie; Jackers, Pascale ULg; Castronovo, Vincenzo ULg

in Belgian Journal of Zoology (1997), 127(issue 1), 3-11

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See detailAntisense galectin-3 alters thymidine incorporation in human MDA-MB435 breast cancer cells
van den Brûle, Frédéric; Bellahcene, Akeila ULg; Jackers, Pascale ULg et al

in International Journal of Oncology (1997), 11(2), 261-264

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See detailIdentification of the active gene coding for the metastasis-associated 37LRP/p40 multifunctional protein.
Clausse, Nathalie; Jackers, Pascale ULg; Jares, P. et al

in DNA & Cell Biology (1996), 15(12), 1009-23

A 37LRP/p40 polypeptide is of major interest because it is consistently up-regulated in cancer cells in correlation with their invasive and metastatic phenotype. Furthermore, this polypeptide presents ... [more ▼]

A 37LRP/p40 polypeptide is of major interest because it is consistently up-regulated in cancer cells in correlation with their invasive and metastatic phenotype. Furthermore, this polypeptide presents intriguing multifunctional properties because it has been characterized as the precursor of the metastasis-associated 67-kD laminin receptor (67LR) and as a cytoplasmic ribosomal-associated protein. The isolation of the 37LRP/p40 gene is a prerequisite for identifying the molecular mechanisms responsible for the constant up-regulation of the 67LR expression in cancer cells. To date, the active 37LRP/p40 gene has never been identified in any species due to the existence of multiple pseudogenes in most vertebrates genomes. In this study, we report for the first time the gene structure and potential regulatory sequences of the 37 LRP/p40 gene. The chicken genome was selected to undergo this characterization because it is the only known vertebrate that bears a single 37 LRP/p40 gene copy. The 37 LRP/p40 active gene is composed of 7 exons and 6 introns and bears features characteristic of a ribosomal protein gene. It does not bear a classical TATA box and it exhibits several transcription initiation sites as demonstrated by RNase protection assay and primer extension. Analysis of potential regulatory regions suggests that gene expression is driven not only by the 5' genomic region but also by the 5' untranslated and intron 1 sequences. On the basis of gene structure and extensive protein evolutionary study, we found that the carboxyterminal domain of the protein is a conserved lock-and-key structure/function domain that could be involved in the biosynthesis of the higher-molecular-weight 67-kD laminin receptor in vertebrates, whereas the central core of the protein would be responsible for the ribosome associated function. The first identification of the active 37LRP/p40 gene presented in this study is a critical step toward the isolation of the corresponding human gene and the understanding of the molecular mechanisms involved in the up-regulation of its expression during tumor invasion and metastasis. [less ▲]

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See detailIsolation from a multigene family of the active human gene of the metastasis-associated multifunctional protein 37LRP/p40 at chromosome 3p21.3.
Jackers, Pascale ULg; Minoletti, Fabiola; Belotti, Dorina et al

in Oncogene (1996), 13(3), 495-503

The 37 kD precursor of the 67 kD laminin receptor (37LRP) is a polypeptide whose expression is consistently upregulated in aggressive carcinoma. Interestingly, the 37LRP appears to be a multifunctional ... [more ▼]

The 37 kD precursor of the 67 kD laminin receptor (37LRP) is a polypeptide whose expression is consistently upregulated in aggressive carcinoma. Interestingly, the 37LRP appears to be a multifunctional protein involved in the translational machinery and has also been identified as p40 ribosome-associated protein. Although highly conserved cDNAs corresponding to this polypeptide have been isolated from several species including vertebrates, invertebrates, plants and prokaryotes, characterization of any of the corresponding active genes has never been reported. In this study, we have cloned an intron-containing fragment which permitted us to isolate the active 37LRP/p40 human gene. This gene contains seven exons and six introns. Ribonuclease protection experiments suggest multiple transcription start sites. The promoter area does not bear a TATA box but contains four Sp1 sites. The first intron is also GC rich containing five Sp1 sites. Intron 4 contains the full sequence of the small nuclear RNA E2 and two Alu sequences are found in intron 3. Fluorescent in situ hybridization localized the 37LRP/p40 active gene on chromosome 3 in the locus 3p21.3 which, interestingly, is a hot spot for genetic alterations in several cancers and particularly in small cell lung carcinoma. [less ▲]

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See detailDecreased expression of galectin-3 is associated with progression of human breast cancer.
Castronovo, Vincenzo ULg; van den Brule, Frédéric; Jackers, Pascale ULg et al

in Journal of Pathology (The) (1996), 179(1), 43-48

Galectin-3, a member of the beta-galactoside-binding lectin family, is involved in several biological events including binding to the basement membrane glycoprotein laminin. Although the exact role of ... [more ▼]

Galectin-3, a member of the beta-galactoside-binding lectin family, is involved in several biological events including binding to the basement membrane glycoprotein laminin. Although the exact role of galectin-3 during the interactions between cells and laminin is not yet known, it has recently been observed that its expression is down-regulated at both the protein and the mRNA level in colon cancer tissues in correlation with progression of the disease. This study investigated the possibility that breast cancer cells might also exhibit decreased galectin-3 expression in association with their aggressiveness. The expression of galectin-3 was examined by immunoperoxidase staining, using a polyclonal antibody raised against recombinant galectin-3, in a collection of 98 human breast lesions including 12 fibroadenomas, 15 fibrocystic disease lesions, 22 in situ carcinomas, and 49 infiltrating ductal carcinomas, 19 of which had positive axillary lymph nodes. Normal breast tissue adjacent to the lesions was present in 59 biopsies. Normal breast tissue expressed high levels (3+) of galectin-3. High expression (2+ to 3+) was also found in most benign lesions examined. The expression of galectin-3 was significantly decreased in in situ carcinoma and this down-regulation was more pronounced in invasive ductal carcinoma, particularly when associated with infiltration of axillary lymph nodes. These data constitute the first observation that galectin-3 is down-regulated in breast cancer and suggest the decreased expression of this galactoside-binding lectin is associated with the acquisition of the invasive and metastatic phenotype. [less ▲]

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See detailSeventeen copies of the human 37 kDa laminin receptor precursor/p40 ribosome-associated protein gene are processed pseudogenes arisen from retropositional events
Jackers, Pascale ULg; Clausse, Nathalie; Fernandez, Maria-Teresa et al

in Biochimica et Biophysica Acta (1996), 1305(1-2), 98-104

A cDNA coding for a 37 kDa polypeptide has been identified in several species as both the potential precursor of the 67 kDa laminin receptor (37LRP) and a putative ribosome-associated protein (p40 ... [more ▼]

A cDNA coding for a 37 kDa polypeptide has been identified in several species as both the potential precursor of the 67 kDa laminin receptor (37LRP) and a putative ribosome-associated protein (p40). Interestingly, increased expression of this polypeptide (37LRP/p40) is consistently observed in invasive and metastatic cancer cells and is associated with poor prognosis. Southern-blot analysis of human genomic DNA predicted multiple copies of the 37LRP/p40 gene. In this study, we report that the number of copies of this sequence in the human genome is 26 +/- 2. We have sequenced and analyzed 19 genomic clones corresponding to the 37LRP/p40 gene and found that they were all processed pseudogenes. They all lack intronic sequences and show multiple genetic alterations leading in some cases to the appearance of stop codons. Moreover, they all bear characteristic features of retroposons as the presence of a poly(A)-tail at their 3' end and short direct repeated flanking DNA sequences. None of the pseudogenes analyzed present cis-elements in their 5' flanking region such as TATA or GC boxes. Our date reveal that over 50% of the 37LRP/p40 gene copies are pseudogenes most probably generated by retropositional events. The finding of multiple pseudogenes for the 37LRP/p40 suggests that the accumulation of several copies of this gene might have given a survival advantage to the cell in the course of evolution. [less ▲]

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