Identification of a Caspase-9 Substrate and Detection of Its Cleavage in Programmed Cell Death during Mouse Development

Nakanishi, Kazuyoshi; Maruyama, Masumi; Shibata, Takehiko; Morishima, Nobuhiro

doi:10.1074/jbc.m105648200

Cited by 78 publications

(74 citation statements)

References 47 publications

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“…The alternative pathway cannot be attributed to caspase-7, because the inhibitor DEVD also blocks this caspase (83). Caspase-9 substrates other than effector caspases-3 and -7 have already been described, such as vimentin (84). Activated caspase-9 was also found within the nucleus of dying cells, raising the possibility of additional nuclear substrates (85).…”

Section: Caspase-9 Induces An Alternative Pathway Of Cell Death Inmentioning

confidence: 97%

Alternative Programs of Cell Death in Developing Retinal Tissue

Guimarães

Benchimol

Amarante-Mendes

et al. 2003

Journal of Biological Chemistry

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We examined cell death in developing retinal tissue, following inhibition of protein synthesis, which kills undifferentiated post-mitotic cells. Ultrastructural features were found of both apoptosis and autophagy. Only approximately half of the degenerating cells were either terminal dUTP nick-end labeling (TUNEL)-positive or reacted with antibodies specific for activated caspases-3 or -9. Bongkrekic acid completely inhibited any appearance of cell death, whereas inhibitors of autophagy, caspases-9 or -3, prevented only TUNEL-positive cell death. Interestingly, inhibition of caspase-6 blocked TUNEL-negative cell death. Simultaneous inhibition of caspases-9 and -6 prevented cell death almost completely, but degeneration dependent on autophagy/ caspase-9 still occurred under inhibition of both caspases-3 and -6. Thus, inhibition of protein synthesis induces in the developing retina various post-translational, mitochondria-dependent pathways of cell death. Autophagy precedes sequential activation of caspases-9 and -3, and DNA fragmentation, whereas, in parallel, caspase-6 leads to a TUNEL-negative form of cell death.

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Section: Caspase-9 Induces An Alternative Pathway Of Cell Death Inmentioning

confidence: 97%

Alternative Programs of Cell Death in Developing Retinal Tissue

Guimarães

Benchimol

Amarante-Mendes

et al. 2003

Journal of Biological Chemistry

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“…The predominant death mechanism in the interdigits is apoptosis (Garcia-Martinez et al, 1993), but syndactyly is never observed by blocking a single molecular component of the apoptotic machinery.Consistent, with the apoptotic nature of cell death, numerous caspases (cysteineaspartic proteases), including initiator (caspase2, caspase 8, and caspase 9) and executioner caspases (caspase 3, caspase 6 and caspase 7; Fig. 2) are upregulated in the regressing interdigits (Nakanishi et al, 2001;Zuzarte-Luis et al, 2006), but interdigital cell death is not blocked in mice bearing single or compound caspase mutations, or deficient in caspase-activating adaptor protein, APAF-1 (Lakhani et al, 2006;Chautan et al, 1999;Kuida et al, 1998;Wang and Lenardo 2000;Nagasaka et al, 2009). It has been proposed that this apparent discrepancy is because interdigital mesenchyme die by necrosis if the apoptotic pathway is disrupted (Chautan et al, 1999).…”

Section: Molecular Machinery Of Cell Deathmentioning

confidence: 59%

Interdigital tissue regression in the developing limb of vertebrates

Lorda‐Diez¹,

Montero²,

García‐Porrero³

et al. 2015

Int. J. Dev. Biol.

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Here we have chosen the regression of the interdigital tissue which sculpts the digits from the hand/foot plate in tetrapod embryos to review the most relevant aspects concerning the regulation and biological significance of programmed cell death. We gather abundant information showing that the initiation of the degenerative process is the result of a complex interplay between the different signaling pathways which are also responsible for limb outgrowth and skeletal tissue differentiation, rather than being regulated by a specific signaling pathway. The model further shows that once the death response is triggered, several different routes of cell disruption, including caspase-dependent apoptosis, lysosomal-mediated cell death, and even a cell senescence process, are activated in the interdigits to ensure their elimination. Transcriptional and structural changes accompanying the degenerative process, and their posible contribution to the control of the death process, are also revised in detail. Finally we survey a number of issues still awaiting clarification, such as the functional implication of interdigital cell death as a source of signals acting on the surrounding tissues, as occurs in the so called "regenerative cell death".

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“…At present, Ͼ400 direct substrates of caspase-3 have been identified (Lüthi and Martin, 2007). However, only a few proteins have been reported to be substrates for caspase-9, including vimentin and amyloid ␤-protein precursor (APP) (Lu et al, 2000;Nakanishi et al, 2001). Here we found that antiSema7A staining is a valuable method for the sensitive detection of caspase-9 activity in tissue.…”

Section: Discussionmentioning

confidence: 99%

Caspase-9 Activation Revealed by Semaphorin 7A Cleavage Is Independent of Apoptosis in the Aged Olfactory Bulb

Ohsawa¹,

Hamada²,

Asou³

et al. 2009

J. Neurosci.

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Caspases are essential in multicellular organisms for inducing cell death during normal development and in the immune system. However, caspases can also trigger the degenerative process under certain conditions such as pathophysiological conditions and aging. Here, we identified Semaphorin 7A (Sema7A) as a novel substrate for caspase-9 that can be used to monitor caspase-9 activity in mice, and found nonapoptotic caspase-9 activation in the aged olfactory bulb (OB). Immunostaining of the OB for the caspase-9-cleaved form of Sema7A revealed abundant caspase-9-activated cells in 2-year-old (aged) but not in 2-month-old (young) mice. In fact, various regions of the aged brain, including the OB, exhibited an increased level of caspase-9 activity. However, the number of dying cells in the aged OB was, intriguingly, much lower (Ͻ20%) than in the OB of young mice. Furthermore, we found that the lower number dying cells in the aged OB was accompanied by a decreased expression of procaspase-3. These results suggest a survival strategy for aged OB neurons, which can no longer regenerate, in which the central apoptotic machinery downstream of caspase-9 is inactivated.

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Identification of a Caspase-9 Substrate and Detection of Its Cleavage in Programmed Cell Death during Mouse Development

Cited by 78 publications

References 47 publications

Alternative Programs of Cell Death in Developing Retinal Tissue

Alternative Programs of Cell Death in Developing Retinal Tissue

Interdigital tissue regression in the developing limb of vertebrates

Caspase-9 Activation Revealed by Semaphorin 7A Cleavage Is Independent of Apoptosis in the Aged Olfactory Bulb

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