The 31-kDa Caspase-generated Cleavage Product of p130  Functions as a Transcriptional Repressor of E2A in Apoptotic Cells

Kim, Wook; Kook, Seunghyi; Kim, Dae Joong; Teodorof, Carmen; Song, Woo Keun

doi:10.1074/jbc.m312026200

Cited by 58 publications

(68 citation statements)

References 54 publications

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“…Cleavage of FAK shuts down its survival signal and disrupts focal adhesion architecture [44]. p130Cas cleavage produces a carboxy-terminal fragment, which regulates transcription of p21 cyclin kinase inhibitor, thus contributing to anoikis execution by blocking the cell cycle [45]. Detached cells undergoing caspase-3 cleavage of FAK and p130Cas then experience the final steps of the anoikis programme.…”

Section: Extrinsic Pathwaymentioning

confidence: 99%

Anoikis: an emerging hallmark in health and diseases

Taddei

Giannoni

Fiaschi

et al. 2011

The Journal of Pathology

528

404

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Anoikis is a programmed cell death occurring upon cell detachment from the correct extracellular matrix, thus disrupting integrin ligation. It is a critical mechanism in preventing dysplastic cell growth or attachment to an inappropriate matrix. Anoikis prevents detached epithelial cells from colonizing elsewhere and is thus essential for tissue homeostasis and development. As anchorage-independent growth and epithelial-mesenchymal transition, two features associated with anoikis resistance, are crucial steps during tumour progression and metastatic spreading of cancer cells, anoikis deregulation has now evoked particular attention from the scientific community. The aim of this review is to analyse the molecular mechanisms governing both anoikis and anoikis resistance, focusing on their regulation in physiological processes, as well as in several diseases, including metastatic cancers, cardiovascular diseases and diabetes.

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Section: Extrinsic Pathwaymentioning

confidence: 99%

Anoikis: an emerging hallmark in health and diseases

Taddei

Giannoni

Fiaschi

et al. 2011

The Journal of Pathology

528

404

View full text Add to dashboard Cite

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“…Caspase 3 -dependent cleavage of p130CAS releases a 31kDa fragment that has pro-apoptotic activities. This fragment translocates to the nucleus and heterodimerises with the transcription factors E2A (also known as TCF3) or E47, thereby repressing p21transcription, promoting loss of focal adhesions and inducing cell rounding and cell death 79,80 . Similarly, the proteolytic cleavage of NEDD9 by caspases 3 and/or 7 releases a C-terminal p28 fragment, that in MCF-7 and HeLa cells induces focal adhesion disassembly, cell detachment and apoptosis 81 , in a mechanism similar to that described for p130CAS, implicating binding to E2A and transcriptional repression of p21.…”

Section: Apoptosismentioning

confidence: 99%

Integrin signalling adaptors: not only figurants in the cancer story

et al. 2010

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Current evidence highlights the ability of adaptor (or scaffold) proteins to create signalling platforms that drive cellular transformation upon integrin-dependent adhesion and growth factor receptor activation. The understanding of the biological effects regulated by these adaptors in tumours might be crucial for the identification of novel targets and the development of innovative therapeutic strategies for human cancer. In this review we will discuss the relevance of adaptor proteins in signalling originating from integrin-mediated cell-extracellular matrix (ECM) adhesion and growth factor stimulation within the context of cell transformation and tumour progression.Herein, we will specifically underline the contribution of p130CAS, NEDD9, CRK, and the IPP complex (ILK, PINCH and PARVIN) to cancer, along with the more recently identified p140CAP.

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“…In select contexts, in which MEF2 has alternatively been linked with induction of apoptosis (44), the activity of caspase 3 and resultant cleavage of HDAC4 would be of great interest. Finally, we note that caspase-mediated cleavage of full-length proteins to generate bioactive cleavage products that independently contribute to cell death has been previously described in a number of other systems (45,46). In addition to cell death, caspases play important roles in regulating cell differentiation.…”

Section: Fig 7 Identification Of Potential Caspase Cleavage Sites Imentioning

confidence: 99%

Caspase-mediated Specific Cleavage of Human Histone Deacetylase 4

Liu

Dowling

Yang

et al. 2004

Journal of Biological Chemistry

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Histone deacetylase 4 (HDAC4) is a class II HDAC implicated in controlling gene expression important for diverse cellular functions, but little is known about how its expression and stability are regulated. We report here that this deacetylase is unusually unstable, with a half-life of less than 8 h. Consistent with the instability of HDAC4 protein, its mRNA was also highly unstable (with a half-life of less than 4 h). The degradation of HDAC4 could be accelerated by exposure of cells to ultraviolet irradiation. HDAC4 degradation was not dependent on proteasome or CRM1-mediated export activity but instead was caspase-dependent and was detectable in diverse human cancer lines. Of two potential caspase consensus motifs in HDAC4, both lying within a region containing proline-, glutamic acid-, serine-, and threonine-rich (PEST) sequences, we identified, by site-directed mutagenesis, Asp-289 as the prime cleavage site. Notably, this residue is not conserved among other class IIa members, HDAC5, -7, and -9. Finally, the induced expression of caspase-cleavable HDAC4 led to markedly increased apoptosis. These results therefore unexpectedly link the regulation of HDAC4 protein stability to caspases, enzymes that are important for controlling cell death and differentiation.Histone deacetylases (HDACs) 1 have been increasingly implicated in mediating diverse fundamental cellular activities. Based on sequence homology with their yeast orthologs, mammalian HDACs have been divided into three classes. Class I HDACs include HDAC1, -2, -3, -7, -8, and -11, whereas class II HDACs contain HDAC4, -5, -6, -7, -9, and -10 (for recent reviews, see Refs. 1-4). Among class II, HDAC4, -5, -7, and -9 form a subclass known as class IIa, whereas HDAC6 and -10 constitute class IIb. A third class of mammalian HDACs includes the Sir2-like proteins Sirt1-7 (5, 6). The most well characterized function of HDACs is the deacetylation of core histones, which in turn leads to the compaction of nucleosomes to repress gene transcription. HDACs have also been implicated in the deacetylation of nonhistone targets. For example, HDAC6 regulates the deacetylation of tubulin, which may in turn promote cell motility (7-9).Despite the increasing repertoire of cellular activities that have been found to involve HDACs, relatively little is known regarding mechanisms regulating their expression. For example, HDAC1 binding to the CCAAT/enhancer-binding protein ␣-promoter increased upon treatment of cells with a proteasome inhibitor, but the protein levels were not directly assessed (10). HDAC5 and HDAC6 are ubiquitinated, but it is unclear how their stability is regulated (11). Interestingly, HDAC1 and HDAC4 undergo sumoylation, a post-translational modification that is reminiscent of ubiquitination but does not appear to regulate protein degradation (12, 13).To assess how the levels of HDAC4 and other HDACs might be controlled, we measured their protein stability following the inhibition of de novo synthesis. HDAC4 was found to be exceptionally unstable, with a h...

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The 31-kDa Caspase-generated Cleavage Product of p130 Functions as a Transcriptional Repressor of E2A in Apoptotic Cells

Cited by 58 publications

References 54 publications

Anoikis: an emerging hallmark in health and diseases

Anoikis: an emerging hallmark in health and diseases

Integrin signalling adaptors: not only figurants in the cancer story

Caspase-mediated Specific Cleavage of Human Histone Deacetylase 4

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