Caspase Activity Mediates the Differentiation of Embryonic Stem Cells

Fujita, Jun; Crane, Ana M.; Souza, Marlon K.; Déjosez, Marion; Kyba, Michael; Flavell, Richard A.; Thomson, James A.; Zwaka, Thomas P.

doi:10.1016/j.stem.2008.04.001

Cited by 256 publications

(271 citation statements)

References 35 publications

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“…Previous work in mES cells by the group highlighted here found that in addition to promoting Oct4 turnover, ubiquitination also significantly represses the transcriptional activity of Oct4 in vitro [10]. Other posttranscriptional mechanisms reported in ES cells include microRNA targeting of Nanog, Oct4, and Sox2, as well as targeted cleavage of Nanog by Caspase-3 and -9 [11,12]. However, these mechanisms differ fundamentally from the current study in that they function to suppress pluripotency and are active during early differentiation.…”

mentioning

confidence: 51%

OCT4: Less is more

Wagner

Cooney

2009

Cell Res

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mentioning

confidence: 51%

OCT4: Less is more

Wagner

Cooney

2009

Cell Res

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“…These studies present a global approach to characterize the kinetics of protease-substrate pairs in their native states allowing us to prioritize substrates for this important class of posttranslational modifications. Interestingly, in addition to their roles in apoptosis, transient caspase activation occurs during cellular differentiation, including the transformations of monocytes to macrophages and pluripotent stem cells to more specialized cell types (25,26). Perhaps these rapidly cleaved substrates are also important during transient caspase activation in differentiation.…”

Section: Resultsmentioning

confidence: 99%

Global kinetic analysis of proteolysis via quantitative targeted proteomics

Agard

Mahrus

Trinidad

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

124

152

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Mass spectrometry-based proteomics is a powerful tool for identifying hundreds to thousands of posttranslational modifications in complex mixtures. However, it remains enormously challenging to simultaneously assess the intrinsic catalytic efficiencies (k cat ∕K M ) of these modifications in the context of their natural interactors. Such fundamental enzymological constants are key to determining substrate specificity and for establishing the timing and importance of cellular signaling. Here, we report the use of selected reaction monitoring (SRM) for tracking proteolysis induced by human apoptotic caspases-3, -7, -8, and -9 in lysates and living cells. By following the appearance of the cleaved peptides in lysate as a function of time, we were able to determine hundreds of catalytic efficiencies in parallel. Remarkably, we find the rates of substrate hydrolysis for individual caspases vary greater than 500-fold indicating a sequential process. Moreover, the rank-order of substrate cutting is similar in apoptotic cells, suggesting that cellular structures do not dramatically alter substrate accessibility. Comparisons of extrinsic (TRAIL) and intrinsic (staurosporine) inducers of apoptosis revealed similar substrate profiles, suggesting the final proteolytic demolitions proceed by similarly ordered plans. Certain biological processes were rapidly targeted by the caspases, including multiple components of the endocyotic pathway and miRNA processing machinery. We believe this massively parallel and quantitative label-free approach to obtaining basic enzymological constants will facilitate the study of proteolysis and other posttranslational modifications in complex mixtures.apoptosis | caspase | enzymology | mass spectrometry | selected reaction monitoring A poptosis is a form of programmed cell death that serves to eliminate unnecessary, infected, or tumorigenic cells from eukaryotic organisms. While many intrinsic and extrinsic stimuli can initiate apoptosis, these ultimately converge on the activation of a related family of aspartate-specific cysteine proteases, the caspases, that execute widespread proteolysis and induce noninflammatory death (1). We and others have surveyed N termini that occur in apoptotic cells and collectively reported more than 1,000 caspase-derived cleavages (2-5). This explosion of proteomic data has defined a vast array of caspase substrates proteolyzed during apoptosis. While these data identify caspase targets, and in some cases the sites of proteolysis, they fail to reveal the relative rates of cleavage, a parameter necessary to establish the order of proteolytic events and their importance in extracts and intact cells.The recent application of selected reaction monitoring (SRM) methods, traditionally used for metabolite identification, to proteomic studies has enabled the simultaneous label-free quantification of hundreds of peptides (6, 7). Our development of a N-terminal enrichment platform (3) is ideally suited to the application of SRM to apoptotic proteolysis. Using this platfor...

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“…90 Caspase-7 has an additional role in proper functioning of odontoblasts as caspase-7 knockout mice show reduced dental mineralization. 91 A role for caspase-3 in differentiation of embryonic stem cells (ESCs) and hematopoietic stem cells (HSCs) has also been reported, 92,93 with caspase-3 deficiency-impeding differentiation Haematopoietic stem cell Caspase-3 Maintenance of stem-cell quiescence and response to external stimuli 93 New functions for old molecules S Shalini et al of these stem cell populations. Caspase activity is also required for macrophage colony-stimulating factor (M-CSF)-mediated differentiation of human peripheral blood monocytes.…”

Section: Caspases In Cell-fate Determination and Differentiationmentioning

confidence: 99%

Old, new and emerging functions of caspases

et al. 2014

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Caspases are proteases with a well-defined role in apoptosis. However, increasing evidence indicates multiple functions of caspases outside apoptosis. Caspase-1 and caspase-11 have roles in inflammation and mediating inflammatory cell death by pyroptosis. Similarly, caspase-8 has dual role in cell death, mediating both receptor-mediated apoptosis and in its absence, necroptosis. Caspase-8 also functions in maintenance and homeostasis of the adult T-cell population. Caspase-3 has important roles in tissue differentiation, regeneration and neural development in ways that are distinct and do not involve any apoptotic activity. Several other caspases have demonstrated anti-tumor roles. Notable among them are caspase-2, -8 and -14. However, increased caspase-2 and -8 expression in certain types of tumor has also been linked to promoting tumorigenesis. Increased levels of caspase-3 in tumor cells causes apoptosis and secretion of paracrine factors that promotes compensatory proliferation in surrounding normal tissues, tumor cell repopulation and presents a barrier for effective therapeutic strategies. Besides this caspase-2 has emerged as a unique caspase with potential roles in maintaining genomic stability, metabolism, autophagy and aging. The present review focuses on some of these less studied and emerging functions of mammalian caspases.

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Caspase Activity Mediates the Differentiation of Embryonic Stem Cells

Cited by 256 publications

References 35 publications

OCT4: Less is more

OCT4: Less is more

Global kinetic analysis of proteolysis via quantitative targeted proteomics

Old, new and emerging functions of caspases

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