TSAP6 Facilitates the Secretion of Translationally Controlled Tumor Protein/Histamine-releasing Factor via a Nonclassical Pathway

Amzallag, Nathalie; Passer, Brent J.; Allanic, David; Ségura, Elodie; Théry, Clotilde; Goud, Bruno; Amson, Robert; Telerman, Adam

doi:10.1074/jbc.m404850200

Cited by 192 publications

(191 citation statements)

References 44 publications

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“…First, the protein TCTP does not have a signal sequence (Chitpatima et al 1988;Gross et al 1989), and no precursor protein for TCTP was detected, meaning that TCTP is not secreted through the classical secretory pathway, via the ER and Golgi apparatus. This was confirmed by the finding that its secretion was insensitive to brefeldin A or monensin, two inhibitors of this pathway (Amzallag et al 2004). These authors proposed a non-classical pathway for the secretion of TCTP.…”

Section: Tctp As Extracellular 'Signaling Molecule' In Immune Reactionsmentioning

confidence: 76%

“…Overexpression of TSAP6 did indeed result in increased TCTP levels in exosome preparations and in enhanced secretion of TCTP (Amzallag et al 2004), whereas cells derived from TSAP6-deficient mice are severely compromised in the DNA damage-induced p53-dependent exosomal secretory pathway . Another, also exosome-related pathway for TCTP secretion, was proposed by the Kyunglim Lee's group.…”

Section: Tctp As Extracellular 'Signaling Molecule' In Immune Reactionsmentioning

confidence: 91%

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The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

Bommer

2017

Results and Problems in Cell Differentiation

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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. TCTP is able to interact with a large number of other proteins and is therefore involved in many core cell biological processes, predominantly in the response to cellular stresses, such as oxidative stress, heat shock, genotoxic stress, imbalance of ion metabolism as well as other conditions. Mechanistically, TCTP acts as an anti-apoptotic protein, and it is involved in DNA-damage repair and in cellular autophagy. Thus, broadly speaking, TCTP can be considered a cytoprotective protein. In addition, TCTP facilitates cell division through stabilising the mitotic spindle and cell growth through modulating growth signalling pathways and through its interaction with the proteosynthetic machinery of the cell. Due to its activities, both as an anti-apoptotic protein and in promoting cell growth and division, TCTP is also essential in the early development of both animals and plants. Apart from its involvement in various biological processes at the cellular level, TCTP can also act as an extracellular protein and as such has been involved in modulating whole-body defence processes, namely in the mammalian immune system. Extracellular TCTP, typically in its dimerised form, is able to induce the release of cytokines and other signalling molecules from various types of immune cells. There are also several examples, where TCTP was shown to be involved in antiviral/antibacterial defence in lower animals. In plants, the protein appears to have a protective effect against phytotoxic stresses, such as flooding, draught, too high or low temperature, salt stress or exposure to heavy metals. The finding for the latter stress condition is corroborated by earlier reports that TCTP levels are considerably up-regulated upon exposure of earthworms to high levels of heavy metals. Given the involvement of TCTP in many biological processes aimed at maintaining cellular or whole-body homeostasis, it is not surprising that dysregulation of TCTP levels may promote a range of disease processes, foremost cancer. Indeed a large body of evidence now supports a role of TCTP in at least the most predominant types of human cancers. Typically, this can be ascribed to both the anti-apoptotic activity of the protein and to its function in promoting cell growth and division. However, TCTP also appears to be involved in the later stages of cancer progression, such ...

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Section: Tctp As Extracellular 'Signaling Molecule' In Immune Reactionsmentioning

confidence: 76%

Section: Tctp As Extracellular 'Signaling Molecule' In Immune Reactionsmentioning

confidence: 91%

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

Bommer

2017

Results and Problems in Cell Differentiation

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“…More recently the p53-regulated TSAP-6 gene was shown to enhance the rate of exosome production from cells undergoing a p53 response to stress. 56 Exosomes also can communicate with other cells both in the immune system and cells in its own vicinity. Cells in stress will want to coordinate their responses with the surrounding cell layer in vivo and this is a new field opening up to future research efforts.…”

Section: The Downstream Events In the P53 Pathwaymentioning

confidence: 99%

“…In addition p53 activation can enhance the rate of exosome production by the damaged cell by inducing the p53-regulated TSAP-6 gene. 56,61 Exosomes can communicate with adjacent cells by cell fusion and with T cells by presenting antigens to the immune system. Could p53-mediated apoptosis enhance immunization of the host in this fashion?…”

Section: The Cellular Outputs Of the Downstream Eventsmentioning

confidence: 99%

The P53 pathway: what questions remain to be explored?

2006

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The p53 pathway is composed of hundreds of genes and their products that respond to a wide variety of stress signals. These responses to stress include apoptosis, cellular senescence or cell cycle arrest. In addition the p53-regulated genes produce proteins that communicate these stress signals to adjacent cells, prevent and repair damaged DNA and create feedback loops that enhance or attenuate p53 activity and communicate with other signal transduction pathways. Many questions remain to be explored in our understanding of how this network of genes plays a role in protection from cancers, therapy and integrating the homeostatic mechanisms of stress management and fidelity in a cell and organism. The goal of this chapter is to elucidate some of those questions and suggest new directions for this area of research.

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“…38-41 Therefore, we tested whether the reconstitution of endogenous p53 amounts on E6/E7 repression (Fig. 2a) was linked to the stimulation of these genes in HeLa cells.…”

Section: Inhibition Of E6/e7 Expression Increases the Amounts Of Exosmentioning

confidence: 99%

Silencing of human papillomavirus (HPV) E6/E7 oncogene expression affects both the contents and the amounts of extracellular microvesicles released from HPV‐positive cancer cells

Honegger

Leitz

Bulkescher

et al. 2013

Intl Journal of Cancer

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The human papillomavirus (HPV) E6/E7 oncogenes play a crucial role in the HPV-induced carcinogenesis. In this study, the authors investigated whether silencing of endogenous HPV E6/E7 expression may influence the contents or amounts of extracellular microvesicles (eMVs) released from HPV-positive cancer cells. It was found that eMVs secreted from HeLa cells are enriched for Survivin protein. RNA interference studies revealed that maintenance of both intracellular and microvesicular Survivin amounts was strongly dependent on continuous E6/E7 expression. This indicates that intracellular HPV activities are translated into visible alterations of protein contents in eMVs. Besides Survivin, eMVs from HeLa cells contain additional members of the inhibitor of apoptosis protein (IAP) family (XIAP, c-IAP1 and Livin). In contrast, no evidence for the presence of the HPV E6 and E7 oncoproteins in eMVs was obtained. Moreover, it was found that silencing of HPV E6/E7 expression led to a significant increase of exosomes-representing eMVs of endocytic origin-released from HeLa cells. This effect was associated with the reinduction of p53, stimulation of the p53 target genes TSAP6 and CHMP4C that can enhance exosome production and induction of senescence. Taken together, these results show that silencing of HPV E6/E7 oncogene expression profoundly affects both the composition and amounts of eMVs secreted by HPV-positive cancer cells. This indicates that HPVs can induce molecular signatures in eMVs that may affect intercellular communication and could be explored for diagnostic purposes.Specific types of human papillomaviruses (HPVs), such as HPV16 and HPV18, cause cervical cancer and are closely linked to the development of additional human malignancies in the oropharyngeal and anogenital regions. 1 The viral E6 and E7 oncoproteins are crucial both for the HPV-associated induction of transformation and for the maintenance of the tumorigenic phenotype of HPV-positive cervical cancer cells. 2,3 E6 and E7 dysregulate intracellular pathways involved in the control of cellular proliferation, apoptosis and genetic stability. For example, E6 induces the proteolytic degradation of the p53 tumor suppressor protein 4 and stimulates telomerase activity, 5 whereas E7 interferes with the activity of the retinoblastoma tumor suppressor protein, pRb, and other pocket proteins. 6 In contrast to the increasing understanding of the intracellular activities of the viral E6/E7 oncogenes, surprisingly little is known about possible effects on the intercellular communication of HPV-positive cancer cells.Extracellular microvesicles (eMVs) include exosomes that are small vesicles (50-100 nm in diameter) of endosomal origin secreted by a variety of cells, including tumor cells. 7 Exosomes have recently gained much interest in oncology, particularly due to three properties: (i) exosomes secreted from tumor cells can suppress the immune response toward the tumor, 8,9 (ii) tumor cell-derived exosomes can accelerate tumor growth and invasiveness by horizon...

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TSAP6 Facilitates the Secretion of Translationally Controlled Tumor Protein/Histamine-releasing Factor via a Nonclassical Pathway

Cited by 192 publications

References 44 publications

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

The P53 pathway: what questions remain to be explored?

Silencing of human papillomavirus (HPV) E6/E7 oncogene expression affects both the contents and the amounts of extracellular microvesicles released from HPV‐positive cancer cells

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