Big wheel keeps on turning: apoptosome regulation and its role in chemoresistance

Fadeel, Bengt; Ottosson, Astrid; Pervaiz, Shazib

doi:10.1038/sj.cdd.4402265

Cited by 79 publications

(80 citation statements)

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“…Another apoptotic mechanism affected by TCTP is the formation of the apoptosome. A core component of this structure is the apoptotic protease activating factor (Apaf-1), whose inactivation has been implicated in carcinogenesis and the development of anticancer drug resistance (Fadeel et al 2008). A recent report by the group of Kyunglim Lee documented that TCTP binds to Apaf-1 via its caspase recruitment domain and inhibits the activation of caspase 9 (Jung et al 2014).…”

Section: Stress Responsementioning

confidence: 99%

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: Stress Responsementioning

confidence: 99%

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

Bommer

2017

Results and Problems in Cell Differentiation

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“…10 In cancer development, the activities of apoptotic proteins are defective, and a decrease or increase in the respective expression levels of pro-and antiapoptotic factors is also observed. 4,11 It is well documented that the expression of various apoptotic players is regulated at the level of transcription. 4,[12][13][14] More recent evidence suggests that apoptotic genes are also regulated post-transcriptionally.…”

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confidence: 99%

“…Bad, Bax), by mediating the release of cytochrome c (cyt c) from the mitochondria to the cytoplasm, or inhibit it, by preventing this release (Bcl-2, Bcl-x L ). 4,5 The cytoplasmic localization of cyt c enables the formation of an active apoptosome, a complex bringing together Apaf-1 protein and caspase-9. 4,6 Once active, the apoptosome triggers the activation of caspase-9, allowing it to cleave and activate downstream caspases (such as -3 and -7), leading to cell death.…”

mentioning

confidence: 99%

“…4,5 The cytoplasmic localization of cyt c enables the formation of an active apoptosome, a complex bringing together Apaf-1 protein and caspase-9. 4,6 Once active, the apoptosome triggers the activation of caspase-9, allowing it to cleave and activate downstream caspases (such as -3 and -7), leading to cell death. 4 Not surprisingly, caspase-9 has been characterized as an important regulator of caspase-mediated apoptosis.…”

mentioning

confidence: 99%

“…4,6 Once active, the apoptosome triggers the activation of caspase-9, allowing it to cleave and activate downstream caspases (such as -3 and -7), leading to cell death. 4 Not surprisingly, caspase-9 has been characterized as an important regulator of caspase-mediated apoptosis. [7][8][9] The activity of the apoptosome may be either increased by activators such as pp32/ PHAPI or decreased by inhibitors such as prothymosin a (ProT).…”

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confidence: 99%

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Apoptotic-induced cleavage shifts HuR from being a promoter of survival to an activator of caspase-mediated apoptosis

et al. 2012

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Little is known about the cellular mechanisms modulating the shift in balance from a state of survival to cell death by caspasemediated apoptosis in response to a lethal stress. Here we show that the RNA-binding protein HuR has an important function in mediating this switch. During caspase-mediated apoptosis, HuR is cleaved to generate two cleavage products (CPs). Our data demonstrate that the cleavage of HuR switches its function from being a prosurvival factor under normal conditions to becoming a promoter of apoptosis in response to a lethal stress. In the absence of an apoptotic stimuli, HuR associates with and promotes the expression of caspase-9 and prothymosin a (ProT) mRNAs, and pro-and antiapoptotic factors, respectively, both of which have been characterized as important players in determining cell fate. During the early steps of caspase-mediated apoptosis, however, the level of caspase-9 protein increases, while ProT remains unchanged. Under these conditions, the two HuR-CPs selectively bind to and stabilize caspase-9 mRNA, but do not bind to ProT. Hence, taken together, our data show that by maintaining a threshold of expression of proapoptotic factors such as caspase-9 in response to a lethal stress, the HuR-CPs help a cell to switch from resisting death to undergoing apoptosis.

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The Apoptosome: The Executioner of Mitochondria‐mediated Apoptosis

Ferraro

Cecconi

2009

Encyclopedia of Life Sciences

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The apoptosome is a molecular complex of two major components – the adapter protein apoptotic protease activating factor 1 ( Apaf1 ) and the protease caspase‐9. These are assembled during apoptosis upon Apaf1 interaction with cytochrome c , which is released from the intermembrane space of mitochondria under precise cell death stimuli. Apoptosome assembly triggers effector caspase activation, which – in turn – drives cell demise. Several proteins bind and regulate apoptosome. This complex is found in vertebrates, even though similar functions are played by ortholog proteins through slightly different mechanisms also in lower eukaryotes. Given the involvement of apoptosome dysfunctions in human diseases, this complex is also a relevant molecular target in biomedicine. Key concepts It was a stunning discovery to find out that cytochrome c , essential for adenosine triphosphate (ATP) production and cell life, was involved in a cell death pathway. Apoptosis regulation is essential for avoiding unwanted cell death and allowing the correct development and homoeostasis of the whole organism. Therefore there are several regulators of apoptosome activity. Caspases and Apaf1 have a key phylogenetically conserved role in apoptosis. Apoptosis is evolutionary well‐conserved in terms of its basic mechanisms; however, the role of mitochondria in apoptosis of organisms other than vertebrates needs to be clearly defined.

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Big wheel keeps on turning: apoptosome regulation and its role in chemoresistance

Cited by 79 publications

References 111 publications

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

Apoptotic-induced cleavage shifts HuR from being a promoter of survival to an activator of caspase-mediated apoptosis

The Apoptosome: The Executioner of Mitochondria‐mediated Apoptosis

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