TCTP/tpt1 - Remodeling Signaling from Stem Cell to Disease

Ulrich-Axel Bommer

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 as invasion and metastasis. Hence, high TCTP levels in tumour tissues are often associated with a poor patient outcome. Due to its multiple roles in cancer progression, TCTP has been proposed as a potential target for the development of new anti-cancer strategies in recent pilot studies. Apart from its role in cancer, TCTP dysregulation has been reported to contribute to certain processes in the development of diabetes, as well as in diseases associated with the cardiovascular system.Since cellular TCTP levels are highly regulated, e.g. in response to cell stress or to growth signalling, and because deregulation of this protein contributes to many disease processes, a detailed understanding of regulatory processes that impinge on TCTP levels is required. The last section of this chapter summarises our current knowledge on the mechanisms that may be involved in the regulation of TCTP levels. Essentially, expression of the TPT1 gene is regulated at both the transcriptional and the translational level, the latter being particularly advantageous when a rapid adjustment of cellular TCTP levels is required, for example in cell stress responses. Other regulatory mechanisms, such as protein stability regulation, may also contribute to the regulation of overall TCTP levels.