Role of TCTP in Cell Biological and Disease Processes.

Translationally controlled tumor protein (TCTP), also referred to as histamine-releasing factor (HRF) or fortilin, is a multifunctional protein, expressed in essentially all eukaryotic organisms [...

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.

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation.

The Translational Controlled Tumour Protein TCTP (gene symbol TPT1, also called P21, P23, Q23, fortilin or histamine-releasing factor, HRF) is a highly conserved protein present in essentially all eukaryotic organisms and involved in many fundamental cell biological and disease processes. It was first discovered about 35 years ago, and it took an extended period of time for its multiple functions to be revealed, and even today we do not yet fully understand all the details. Having witnessed most of this history, in this chapter, I give a brief overview and review the current knowledge on the structure, biological functions, disease involvements and cellular regulation of this protein.

Translationally controlled tumour protein TCTP is induced early in human colorectal tumours and contributes to the resistance of HCT116 colon cancer cells to 5-FU and oxaliplatin.

Background: Translationally controlled tumour protein TCTP is an anti-apoptotic protein frequently overexpressed in cancers, where high levels are often associated with poor patient outcome. TCTP may be involved in protecting cancer cells against the cytotoxic action of anti-cancer drugs. Here we study the early increase of TCTP levels in human colorectal cancer (CRC) and the regulation of TCTP expression in HCT116 colon cancer cells, in response to treatment with the anti-cancer drugs 5-FU and oxaliplatin.

Growth-factor dependent expression of the translationally controlled tumour protein TCTP is regulated through the PI3-K/Akt/mTORC1 signalling pathway.

Translationally controlled tumour protein TCTP (gene symbol: TPT1) is a highly-conserved, cyto-protective protein implicated in many physiological and disease processes, in particular cancer, where it is associated with poor patient outcomes. To understand the mechanisms underlying the accumulation of high TCTP levels in cancer cells, we studied the signalling pathways that control translation of TCTP mRNA, which contains a 5'-terminal oligopyrimidine tract (5'-TOP). In HT29 colon cancer cells and in HeLa cells, serum increases the expression of TCTP two- and four-fold, respectively, and this is inhibited by rapamycin or mTOR kinase inhibitors.

Translationally controlled tumour protein (TCTP) is a novel glucose-regulated protein that is important for survival of pancreatic beta cells.

Aims/hypothesis: This study used proteomics and biochemical approaches to identify novel glucose-regulated proteins and to unveil their role in pancreatic beta cell function. Translationally controlled tumour protein (TCTP) was identified to be one such protein, and further investigations into its function and regulation were carried out.

Methods: Global protein profiling of beta cell homogenates following glucose stimulation was performed using two-dimensional gel electrophoresis.

Roles of the translationally controlled tumour protein (TCTP) and the double-stranded RNA-dependent protein kinase, PKR, in cellular stress responses.

Translationally controlled tumour protein (TCTP) is a highly conserved protein present in all eukaryotic organisms. Various cellular functions and molecular interactions have been ascribed to this protein, many related to its growth-promoting and antiapoptotic properties. TCTP levels are highly regulated in response to various cellular stimuli and stresses.

Re-evaluating the roles of proposed modulators of mammalian target of rapamycin complex 1 (mTORC1) signaling.

Signaling through mammalian target of rapamycin complex 1 (mTORC1) is stimulated by amino acids and insulin. Insulin inactivates TSC1/2, the GTPase-activator complex for Rheb, and Rheb.GTP activates mTORC1.

The translationally controlled tumour protein (TCTP).

The translationally controlled tumour protein (TCTP) is a highly conserved protein that is widely expressed in all eukaryotic organisms. Based on its sequence, TCTP was listed as a separate protein family in protein databases but the recent elucidation of the solution structure of the fission yeast orthologue places it close to a family of small chaperone proteins. The molecular functions determined so far, Ca(2+)- and microtubule-binding, have been mapped to an alpha-helical region of the molecule.

The mRNA of the translationally controlled tumor protein P23/TCTP is a highly structured RNA, which activates the dsRNA-dependent protein kinase PKR.

The dsRNA-activated protein kinase PKR is involved in signal transduction pathways that mediate cellular processes as diverse as cell growth and differentiation, the stress response, and apoptosis. PKR was originally described as an interferon-inducible elF2alpha kinase involved in the antiviral defense mechanism of the cell. The interaction of the kinase with specific viral RNAs has been studied in much detail, but information about cellular mRNAs, which are able to bind and activate PKR, is scarce.

Translational control: the cancer connection.

There is now a growing body of evidence which suggests links between the regulation of protein synthesis and the disruption of cell behaviour that typifies cancer. This directed issue of the International Journal of Biochemistry and Cell Biology presents several review articles of relevance to this field. The topics covered include the significance of the regulation and overexpression of polypeptide chain initiation factors for cell transformation and malignancy, the role of mRNA structure in the control of synthesis of key growth regulatory proteins, the actions of the eIF2 alpha-specific protein kinase PKR in the control cell growth and apoptosis, and the involvement of the elongation factor eEF1 in oncogenesis.

The growth-related, translationally controlled protein P23 has properties of a tubulin binding protein and associates transiently with microtubules during the cell cycle.

The translationally controlled protein P23 was discovered by the early induction of its rate of synthesis after mitogenic stimulation of mouse fibroblasts. P23 is expressed in almost all mammalian tissues and it is highly conserved between animals, plants and yeast. Based on its amino acid sequence, P23 cannot be attributed to any known protein family, and its cellular function remains to be elucidated.

Translational regulation of the mammalian growth-related protein P23: involvement of eIF-4E.

Synthesis of the mammalian growth-related protein P23 is rapidly induced after serum stimulation of mouse fibroblasts and Ehrlich ascites tumour cells. This induction occurs at the translational level. Growth-induction leads also to an increase in phosphorylation of the rate-limiting initiation factor eIF-4E.

Amino acid sequence analysis of the beta- and gamma-subunits of eukaryotic initiation factor eIF-2. Identification of regions interacting with GTP.

By affinity labelling using two different GTP photoaffinity analogues we previously demonstrated that both the beta- and gamma-subunits of eukaryotic initiation factor eIF-2 are involved in GTP binding (Bommer, U.-A. and Kurzchalia, T.

Eukaryotic initiation factors eIF-2 and eIF-3: interactions, structure and localization in ribosomal initiation complexes.

More than ten different protein factors are involved in initiation of protein synthesis in eukaryotes. For binding of initiator tRNA and mRNA to the 40S ribosomal subunit, the initiation factors eIF-2 and eIF-3 are particularly important. They consist of several different subunits and form stable complexes with the 40S ribosomal subunit.

The 5'-untranslated region of p23 mRNA from the Ehrlich ascites tumor is involved in translation control of the growth related protein p23.

The growth-related protein p23 of the Ehrlich ascites tumor (EAT) is preferentially expressed in the exponentially growing tumor; its synthesis is translationally controlled. p23 mRNA is efficiently translated in the wheat germ cell-free lysate. In contrast, p23 mRNA present in poly(A)+RNA isolated from EAT is not translated in cell-free systems of EAT and reticulocytes.

GTP interacts through its ribose and phosphate moieties with different subunits of the eukaryotic initiation factor eIF-2.

We have previously shown that a GTP derivative bearing p-azidoaniline at the gamma-phosphate group specifically labels the gamma-subunit of eukaryotic initiation factor eIF-2. In the present study a new GTP derivative carrying the photoreactive group at the ribose moiety of GTP was applied for affinity labeling of eIF-2 in different initiation complexes. Using this GTP analogue the beta-subunit of eIF-2 was found to be specifically labeled in all complexes investigated.

Identification of proteins of the 40 S ribosomal subunit involved in interaction with initiation factor eIF-2 in the quaternary initiation complex by means of monospecific antibodies.

Monospecific polyclonal antibodies against seven proteins of the 40 S subunit of rat liver ribosomes were used to identify ribosomal proteins involved in interaction with initiation factor eIF-2 in the quaternary initiation complex [eIF-2 X GMPPCP X [3H]Met-tRNAf X 40 S ribosomal subunit]. Dimeric immune complexes of 40 S subunits mediated by antibodies against ribosomal proteins S3a, S13/16, S19 and S24 were found to be unable to bind the ternary initiation complex [eIF-2 X GMPPCP X [3H]Met-tRNAf]. In contrast, 40 S dimers mediated by antibodies against proteins S2, S3 and S17 were found to bind the ternary complex.

Shape and location of eukaryotic initiation factor eIF-2 on the 40S ribosomal subunit of rat liver. Immunoelectron-microscopic and hydrodynamic investigations.

The location of initiation factor eIF-2 and of its subunits in quaternary initiation complexes (40S-ribosomal-subunit.eIF-2. GuoPP[CH2]P.

Affinity labeling by a photoreactive GTP analogue of the delta-subunit of eukaryotic initiation factor eIF-2 in different initiation complexes.

The interaction of GTP with initiation factor eIF-2 in different complexes was studied by affinity labeling using a derivative of [3H]GTP carrying a photoreactive group in the alpha-phosphate moiety. In the binary complex [eIF-2.GTP analogue], in the ternary complex [eIF-2.

Immunofluorescent localization of protein synthesis components in mouse embryo fibroblasts.

The distribution of initiation factor 2(eIF-2) and elongation factor 2(EF-2) in cultured mouse embryo fibroblasts was studied and compared with the distribution of ribosomes. We used immunofluorescence microscopy with monospecific antibodies to eIF-2, EF-2, and proteins S3a and S7 of the small ribosomal subunit. Ribosomes and factors eIF-2 and EF-2 were found mainly in the vicinity of the cell nucleus.

The role of the cytosolic fraction and of initiation factor eIF-2 for changes of the rate of protein synthesis during liver regeneration.

The protein synthesis-stimulating activity of the cytosolic fraction from regenerating rat liver was tested in a cell-free system using washed polysomes from normal rat liver. This activity undergoes significant changes during liver regeneration after partial hepatectomy (p.h.