Dysregulation of TCTP in Biological Processes and Diseases

Translationally controlled tumor protein (TCTP), also called histamine releasing factor (HRF) or fortilin, is a multifunctional protein present in almost all eukaryotic organisms. TCTP is involved in a range of basic cell biological processes, such as promotion of growth and development, or cellular defense in response to biological stresses. Cellular TCTP levels are highly regulated in response to a variety of physiological signals, and regulatory mechanism at various levels have been elucidated. Given the importance of TCTP in maintaining cellular homeostasis, it is not surprising that dysregulation of this protein is associated with a range of disease processes. Here, we review recent progress that has been made in the characterisation of the basic biological functions of TCTP, in the description of mechanisms involved in regulating its cellular levels and in the understanding of dysregulation of TCTP, as it occurs in disease processes such as cancer

Topoisomerase II is regulated by translationally controlled tumor protein for cell survival during organ growth in Drosophila.

Regulation of cell survival is critical for organ development. Translationally controlled tumor protein (TCTP) is a conserved protein family implicated in the control of cell survival during normal development and tumorigenesis. Previously, we have identified a human Topoisomerase II (TOP2) as a TCTP partner, but its role in vivo has been unknown. To determine the significance of this interaction, we examined their roles in developing Drosophila organs. Top2 RNAi in the wing disc leads to tissue reduction and caspase activation, indicating the essential role of Top2 for cell survival. Top2 RNAi in the eye disc also causes loss of eye and head tissues. Tctp RNAi enhances the phenotypes of Top2 RNAi. The depletion of Tctp reduces Top2 levels in the wing disc and vice versa. Wing size is reduced by Top2 overexpression, implying that proper regulation of Top2 level is important for normal organ development. The wing phenotype of Tctp RNAi is partially suppressed by Top2 overexpression. This study suggests that mutual regulation of Tctp and Top2 protein levels is critical for cell survival during organ development

Contribution à l'étude de la génétique moléculaire et de la biologie cellulaire des leucémies

Doctorat en sciences médicalesinfo:eu-repo/semantics/nonPublishe

Etudes moléculaires et fonctionnelles des gènes TSAP6 (Tumor Suppressor Activated Pathway 6) et TCTP (Translationally Controlled Tumor Protein) : cibles pharmacologiques anti-tumorales

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocSudocFranceF

TCTP/tpt1 - Remodeling Signaling from Stem Cell to Disease

International audienceIn this brief introduction, we describe our encounter with TCTP. Back in 2000, we discovered TCTP in two quite different ways: first, we looked at protein partners of TSAP6 and one of them was TCTP. Then, in collaboration with Sidney Brenner, we performed a high-throughput differential screening comparing the parental cancer cells with revertants. The results indicated that TCTP was of the most differentially expressed genes. These two approaches were carried out only months apart. They guided our research and led to the discoveries of drugs that inhibit the function of TCTP. Much of the preclinical data on sertraline as an inhibitor of TCTP in cancer were obtained with Judith Karp at Johns Hopkins. This drug is now given in combination with Ara-C to patients in a phase I clinical trial for Acute Myeloid Leukemia. We will here detail how all this happened in our lab while working around one central project: tumor reversion

The molecular programme of tumour reversion: the steps beyond malignant transformation

International audienceHow cells become malignant has preoccupied scientists for over a century. However, the converse question is also valid: are tumour cells capable of reverting from their malignant state? Askanazy's studies in 1907 indicated that teratoma cells could differentiate into normal somatic tissues and current evidence indicates that some tumour cells have acquired the molecular circuitry that results in the negation of chromosomal instability, translocations, oncogene activation and loss of tumour suppressor genes. Studying these extremely rare events of tumour reversion and deciphering these pathways, which involve SIAH1, presenilin 1, TSAP6 and translationally controlled tumour protein (TCTP), could lead to new avenues in cancer treatment

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Etude structurale des complexes entre TCTP (Translationally Controlled Tumor Protein) et ses partenaires anti-apoptotiques Bcl-xl ou Mcl-1

La thématique du laboratoire de l équipe d Adam Telerman porte sur la réversion tumorale, un processus rare au cours duquel les cellules cancéreuses perdent leur phénotype malin, et deviennent des cellules dites révertantes. Plusieurs protéines clefs impliquées dans cette transformation ont été mises en évidence, dont TCTP (Translationally Controlled Tumor Protein). La protéine TCTP est également impliquée dans la régulation de l apoptose en interagissant et en renforçant l activité anti-apoptotique de Mcl-1 et de Bcl-xl, deux protéines appartenant à la famille des Bcl-2. Ce projet s attache à comprendre en termes moléculaires le mode d action de TCTP au cours de l apoptose. Dans cet objectif nous nous sommes focalisés sur les modes de reconnaissances entre TCTP et ces deux protéines, Mcl-1 et Bcl-xL. Dans ce contexte nous avons développé une collaboration avec l équipe de Jean Cavarelli du département de biologie structurale intégrative de l IGBMC. Notre objectif a consisté à isoler et à caractériser de façon biochimique, biophysique et structurale les complexes TCTP/Mcl-1 et TCTP/Bcl-xl. Nous avons, après optimisation, déterminé les conditions de formation des complexes TCTP/Mcl-1 et TCTP/Bcl-xl. De façon intéressante, ces complexes sont stables à pH basique, faible concentration ionique et favorisés par chauffage. Grâce à une analyse combinée par ultracentrifugation analytique, SEC-MALS et spectrométrie de masse en condition native, nous avons pu déterminer la formation d hétérotétramères de TCTP/Mcl-1 et de TCTP/Bcl-xl. Nous avons également pu identifier les domaines d interaction de ces complexes par mutagénèse dirigée, et montrer que la partie N terminale de TCTP et le sillon hydrophobe de Bcl-xl sont impliqués dans ces interactions. Il s agit de la première caractérisation biochimique et biophysique de complexes impliquant TCTP. Ces données fournissent les premières bases pour l étude structurale de complexes avec TCTP.Adam Telerman s team research focuses on tumor reversion, a rare process in which cancer cells lose their malignant phenotype, and therefore become revertant. Many key proteins were showed to be involved in this transformation, including TCTP (translationally Controlled Tumor Protein). TCTP protein is also involved in apoptosis regulation by interacting and strengthening the anti-apoptotic activity of Mcl-1 and Bcl-xl, two proteins from Bcl-2 family. This work is dedicated to understand the molecular mechanism underlying TCTP action in apoptosis. Here, we focus on TCTP/Mcl-1 and TCTP/Bcl-xl complexes. Within a collaboration with the team of Jean Cavarelli from the department of integrative structural biology at IGBMC we managed to isolate and determine the biochemical properties of these complexes. We showed that TCTP:Mcl1 and TCTP:Bcl-xL have the particularity to be sensitive to pH, ionic strength and temperature. Using analytical ultracentrifugation, SEC-MALS and native mass-spectrometry we were able to characterize both complexes and localize their binding interface. TCTP:Mcl1 and TCTP:Bcl-xL can form heterotetramers, involving the N-terminal part of TCTP and the BH3-groove of Bcl-xL. This work provides the first biophysical and biochemical study of complexes involving TCTP and can be used as a basis for further structural studies on TCTP complexes.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Identification of a 130 Kda bcr related gene product.

International audienceHuman chronic myelogenous leukemia is characterized by a reciprocal translocation between chromosomes 9 and 22. This results in the transfer of the c-abl protooncogene from chromosome 9 into the bcr gene on chromosome 22. The purpose of this study was to characterize the bcr and related gene products. Antibodies were raised against a fused trpE-bcr protein induced in a bacterial expression vector. Immunoprecipitation with the monoclonal and polyclonal antibodies of metabolically [35S]methionine labeled leukemic cell lines shows a 210, 160 and 130 Kda protein in Philadelphia positive cells containing the bcr-abl fused transcript. Only the 160 and 130 Kda were present in the Philadelphia negative cells. In vitro kinase assay shows that the 130 Kda protein is a phosphoprotein mainly phosphorylated on serine. Partial proteolysis indicates that the p210 and p130 share common domains. In subcellular fractionation experiments, the p130 is colocalized with the p210 bcr-abl in the cytoplasmic fraction. Together with the mapping of 4 distinct bcr related loci our data suggest that the 130 Kda phosphoprotein belongs to a wider family of bcr related gene products

Internalization of human T lymphocyte receptors

Monoclonal antibodies specific to human T lymphocyte receptors are currently being used to define the biochemical structure of these proteins as well as of functionally distinct cell subsets. Since one of the antibodies (OKT3) recognizing the T3 (CD3) receptor mimics vital physiological processes involved in the activation of the immune system and has been successfully used as a therapeutical agent, we invesigated one of the mechanisms underlying this antibody-receptor interaction. Our results show that after binding of OKT3, the complex (OKT3-T3) disappears rapidly from the cell surface. Using electron microscopy, we found that this down-regulation is due to the internalization of the complex. Parallel experiments performed on the T11 (CD2) and T4 (CD4)/AIDS retrovirus receptor indicate that the same mechanism applies for the down-regulation of those molecules. These data suggest that the T3, T11 and T4 receptors have a behavior comparable to other well characterized, hormonal and viral receptors; they provide information on the metabolization pathway of surface receptors and on the possible intracellular penetration of ligands like the HTLV-III/LAV agent in human T lymphocytes.SCOPUS: ar.jFLWNAinfo:eu-repo/semantics/publishe