Neural stem cell differentiation is dependent upon endogenous caspase‐3 activity

Fernando, Pasan; Brunette, Steve; Megeney, Lynn A.

doi:10.1096/fj.04-2981fje

Cited by 188 publications

(155 citation statements)

References 51 publications

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“…On the other hand, the importance of caspase activation under nonapoptotic conditions is widely recognized, although the mechanisms regulating caspases in nonapoptotic contexts are largely unknown. For instance, caspase activity is also required for various physiological functions beyond cell death, including sperm individualization, 35 neural stem cell differentiation, 36 osteogenic differentiation of bone marrow stromal stem cells, 37 skeletal muscle differentiation, erythrocyte, keratinocyte, lens differentiation and T-and B-cell proliferation. 38 Erythropoietin was also shown to activate caspase-3 during erythroid differentiation in TF-1 cells, which provides a mechanism for the first time how cells avoid DNA fragmentation with activated caspase-3.…”

Section: Discussionmentioning

confidence: 99%

Multi-sites cleavage of leukemogenic AML1-ETO fusion protein by caspase-3 and its contribution to increased apoptotic sensitivity

et al. 2007

Leukemia

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Leukemia-associated fusion protein AML1-ETO is a product of the chromosome translocation (8;21) frequently occurred in acute myeloid leukemia (AML). The fusion oncoprotein blocks leukemic cell differentiation, and it also induces growth arrest with increased sensitivity to apoptosis induction. Such dichotomous functions make it difficult to clarify the role of AML1-ETO in leukemogenesis. Here, we systematically showed that constitutively and overexpressed AML1-ETO protein was cleaved to four fragments of 70, 49, 40 and 25 kDa by activated caspase-3 during apoptosis induction by extrinsic mitochondrial and death receptor signaling pathways. The in vitro proteolytic system combined with MALDI-TOF/TOF mass spectrometer confirmed that AML1-ETO and wild-type ETO but not RUNX1 (AML1) proteins were direct substrates of apoptosis executioner caspase-3. Site-directed mutagenesis analyses identified two nonclassical aspartates (TMPD 188 and LLLD 368 ) as caspase-3-targeted sites in the AML1-ETO sequence. When these two aspartates were mutated into alanines, more intriguingly, the apoptosis-amplified action of AML1-ETO induction completely disappeared, while inducible expression of the caspase-3-cleaved 70 kDa fragment of AML1-ETO after tetracycline removal is sufficient to enhance apoptotic sensitivity. Further investigations on the potential in vivo effects of such a cleavage and its possible role in leukemogenesis would provide new insights for understanding the biology and treatment of AML1-ETO-associated leukemia.

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Section: Discussionmentioning

confidence: 99%

Multi-sites cleavage of leukemogenic AML1-ETO fusion protein by caspase-3 and its contribution to increased apoptotic sensitivity

et al. 2007

Leukemia

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“…1E), suggesting this as a possible mechanism behind its antiapoptotic role. Also, several studies have implicated caspase3 in nonapoptotic roles in neural development, including promotion of neurogenesis, refinement of neural circuits and synaptic plasticity [46][47][48][49]. Thus we cannot rule out the possibility that LIF, via reduced caspase3, could have affected other aspects of NP cell in vitro differentiation as well.…”

Section: Reduced Apoptosis Correlated To Reduction In Caspases and Rosmentioning

confidence: 93%

Neurotrophic Effects of Leukemia Inhibitory Factor on Neural Cells Derived from Human Embryonic Stem Cells

et al. 2012

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Various growth factor cocktails have been used to proliferate and then differentiate human neural progenitor (NP) cells derived from embryonic stem cells (ESC) for in vitro and in vivo studies. However, the cytokine leukemia inhibitory factor (LIF) has been largely overlooked. Here, we demonstrate that LIF significantly enhanced in vitro survival and promoted differentiation of human ESC-derived NP cells. In NP cells, as well as NP-derived neurons, LIF reduced caspase-mediated apoptosis and reduced both spontaneous and H 2 O 2 -induced reactive oxygen species in culture. In vitro, NP cell proliferation and the yield of differentiated neurons were significantly higher in the presence of LIF. In NP cells, LIF enhanced cMyc phosphorylation, commonly associated with self-renewal/proliferation. Also, in differentiating NP cells LIF activated the phosphoinositide 3-kinase and signal transducer and activator of transcription 3 pathways, associated with cell survival and reduced apoptosis. When differentiated in LIF 1 media, neurite outgrowth and ERK1/2 phosphorylation were potentiated together with increased expression of gp130, a component of the LIF receptor complex. NP cells, pretreated in vitro with LIF, were effective in reducing infarct volume in a model of focal ischemic stroke but LIF did not lead to significantly improved initial NP cell survival over nontreated NP cells. Our results show that LIF signaling significantly promotes human NP cell proliferation, survival, and differentiation in vitro. Activated LIF signaling should be considered in cell culture expansion systems for future human NP cell-based therapeutic transplant studies.

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“…In addition, caspase-3 activation and substrate cleavage has been reported in the absence of cell death in gerbil hypoxia (Garnier et al, 2004) and in ischemic tolerance where neuronal caspase-3 is essential for the neuroprotective effect of preconditioning (Garnier et al 2003;McLaughlin et al, 2003;Tanaka et al, 2004). Furthermore, other studies have also demonstrated a role of caspase-3 in the maturation of cerebellar granular cells during development (Oomman et al, 2004) and the differentiation of neural progenitor cells in the olfactory bulb (Fernando et al, 2005;Yan et al, 2001). Progenitor cells that divide and migrate through the rostral migratory stream en route to the olfactory bulb, show cleaved caspase-3 but no signs of cell death (Yan et al, 2001).…”

Section: Presence Of Caspase-cleaved Gfapmentioning

confidence: 96%

Caspase‐3 activation in astrocytes following postnatal excitotoxic damage correlates with cytoskeletal remodeling but not with cell death or proliferation

Acarín¹,

Villapol²,

Faiz³

et al. 2007

Glia

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Caspase-3 has classically been defined as the main executioner of programmed cell death. However, recent data supports the participation of this protease in non-apoptotic cellular events including cell proliferation, cell cycle regulation, and cellular differentiation. In this study, astroglial cleavage of caspase-3 was analyzed following excitotoxic damage in postnatal rats to determine if its presence is associated with apoptotic cell death, cell proliferation, or cytoskeletal remodeling. A well-characterized in vivo model of excitotoxicity was studied, where damage was induced by intracortical injection of N-methyl-D-asparate (NMDA) in postnatal day 9 rats. Our results demonstrate that cleaved caspase-3 was mainly observed in the nucleus of activated astrocytes in the lesioned hemisphere as early as 4 h postlesion and persisted until the glial scar was formed at 7-14 days, and it was not associated with TUNEL labeling. Caspase-3 enzymatic activity was detected at 10 h and 1 day postlesion in astrocytes, and co-localized with caspasecleaved fragments of glial fibrillary acidic protein (CCP-GFAP). However, at longer survival times, when astroglial hypertrophy was observed, astroglial caspase-3 did not generally correlate with GFAP cleavage, but instead was associated with de novo expression of vimentin. Moreover, astroglial caspase-3 cleavage was not associated with BrdU incorporation. These results provide further evidence for a nontraditional role of caspases in cellular function that is independent of cell death and suggest that caspase activation is important for astroglial cytoskeleton remodeling following cellular injury. V V C 2007 Wiley-Liss, Inc.

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Neural stem cell differentiation is dependent upon endogenous caspase‐3 activity

Cited by 188 publications

References 51 publications

Multi-sites cleavage of leukemogenic AML1-ETO fusion protein by caspase-3 and its contribution to increased apoptotic sensitivity

Multi-sites cleavage of leukemogenic AML1-ETO fusion protein by caspase-3 and its contribution to increased apoptotic sensitivity

Neurotrophic Effects of Leukemia Inhibitory Factor on Neural Cells Derived from Human Embryonic Stem Cells

Caspase‐3 activation in astrocytes following postnatal excitotoxic damage correlates with cytoskeletal remodeling but not with cell death or proliferation

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