Procaspase-3 and Poly(ADP)ribose Polymerase (PARP) Are Calpain Substrates

McGinnis, Kim M.; Gnegy, Margaret E.; Park, Yang Hae; Mukerjee, Neeta; Wang, Kevin

doi:10.1006/bbrc.1999.1315

Cited by 170 publications

(117 citation statements)

References 31 publications

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“…For instance, calpains have been described by some to act upstream of caspase processing, but others implicated them downstream of caspase activation. [49][50][51][52][53][54] Likewise, some found apoptosis induced by FAS ligand to be independent of calpains, but others implicated them in FAS receptormediated apoptosis of neutrophils. 55,56 Our observation that Bfl-1 sensitizes cells to TNF/CHX-induced death, coincident with its proteolytic processing by m-calpain or a calpain-like activity in vivo, is consistent with reports indicating that caspases and calpains can cleave prosurvival Bcl-xL or Bcl-2 proteins leading to the emergence of a prodeath fragment.…”

Section: Discussionmentioning

confidence: 99%

Constitutive proteasome-mediated turnover of Bfl-1/A1 and its processing in response to TNF receptor activation in FL5.12 pro-B cells convert it into a prodeath factor

et al. 2005

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Bfl-1/A1 is generally recognized as a Bcl-2-related inhibitor of apoptosis. We show that Bfl-1 undergoes constitutive ubiquitin/proteasome-mediated turnover. Moreover, while Bfl-1 suppresses apoptosis induced by staurosporine or cytokine withdrawal, it is proapoptotic in response to tumor necrosis factor (TNF) receptor activation in FL5.12 pro-B cells. Its anti-versus proapoptotic effect is regulated by two proteolytic events: (1) its constitutive proteasome-mediated turnover and (2) its TNF/cycloheximide (CHX)-induced cleavage by l-calpain, or a calpain-like activity, coincident with acquisition of a proapoptotic phenotype. In vitro studies suggest that calpain-mediated cleavage of Bfl-1 occurs between its Bcl-2 homology (BH)4 and BH3 domains. This would be consistent with the generation of a proapoptotic Bax-like BH1-3 molecule. Overall, our studies uncovered two new regulatory mechanisms that play a decisive role in determining Bfl-1's prosurvival versus prodeath activities. These findings might provide important clues to counteract chemoresistance in tumor cells that highly express Bfl-1.

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Section: Discussionmentioning

confidence: 99%

Constitutive proteasome-mediated turnover of Bfl-1/A1 and its processing in response to TNF receptor activation in FL5.12 pro-B cells convert it into a prodeath factor

et al. 2005

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“…Besides caspasemediated fragments of 86 and 25 kDa, poly-(ADP-ribose) polymerase (PARP) (113 kDa) can also be cleaved by calpain during apoptosis, generating a 40-kDa peptide. 37 Similarly, fodrin (a-II-spectrin) (240 kDa) undergoes calpain-mediated degradation into 150 and 140 kDa fragments, in addition to the caspase-dependent products of 150 and 120 kDa. 38 In serumstarved 661W photoreceptors, an approximately 40-kDa PARP band and a 140-kDa fodrin band, consequence of calpain activity, were detected by WB (Figure 3c and d).…”

Section: Calcium-dependent Protease M-calpain Is Activated In 661w Cementioning

confidence: 99%

Multiple death pathways in retina-derived 661W cells following growth factor deprivation: crosstalk between caspases and calpains

2005

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During development of the mammalian retina, neurons that do not succeed in establishing functional synaptic connections are eliminated by apoptosis, allowing the formation of a finely tuned network. Growth factors play a crucial role in controlling the balance between apoptosis and survival signals not only at developmental stages but also in longterm preservation of retinal functions. In the present work, we explore the apoptotic mechanisms triggered by growth factor deprivation of retina-derived 661W cells. Under serum starvation conditions, these cone photoreceptors underwent cell death with participation of caspase-9, -3 and -12. Interestingly, inhibition of caspases did not prevent apoptosis but only resulted in a temporary delay. We show m-calpain activation in parallel with caspases, indicating that more than one execution pathway is available to cone photoreceptors. Moreover, crosstalk of the caspase and calpain pathways was detected, suggesting a loop that may act to amplify the apoptotic cascade.

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“…The two major calpain family proteins, µ-calpain and m-calpain, share a 30 kDa regulatory subunit and require different Ca 2+ concentrations for activation in vitro. Activated calpain acts on a host of endogenous proteins, which include cytoskeletal proteins (fodrin, vimentin, keratin, and tau), PARP, calmodulin-dependent protein kinase IV (CaMKIV), clathrin assembly protein, bax, and even procaspase-3 (Ando et al, 1988;Litersky and Johnson, 1995;McGinnis et al, 1998;Prasad et al, 1998;McGinnis et al, 1999a;Kim and Kim, 2001). Particularly, in many neurodegenerative disorders such as Alzheimer's disease, this calpain systems are involved (Patrick et al, 1999;Lee et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Neuronal loss in primary long-term cortical culture involves neurodegeneration-like cell death via calpain and p35 processing, but not developmental apoptosis or aging

Kim

Oh²,

Park³

et al. 2007

Exp Mol Med

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Primary neuronal culture is a powerful tool to study neuronal development, aging, and degeneration. However, cultured neurons show signs of cell death after 2 or 3 weeks. Although the mechanism underlying this phenomenon has not been elucidated, several preventive methods have been identified. Here we show that the neuronal loss in primary cortical culture involves calpain activation and subsequent neuronal cell death. Neuronal loss during cultivation showed destruction of neurites and synapses, and a decrease in neuron numbers. µ-Calpain and m-calpain were initially activated and accumulated by increased RNA expression. This neuronal death exhibited neurodegenerative features, such as conversion of p35 to p25, which is important in the developmental process and in the pathogenesis of Alzheimer's disease. But, postnatal and aged rat cortex did not show calpain activation and prolonged processing of p35 to p25, in contrast to the long-term culture of cortical neurons. In addition, the inhibition of calpains by ALLM or ALLN blocked the conversion of p35 to p25, indicating that the calpain activity is essential for the neurodegenerative features of cell death. Taken together, this study shows that the neuronal loss in primary cortical cultures involves neurodegeneration-like cell death through the activation of calpains and the subsequent processing of p35 to p25, but not developmental apoptosis or aging. Our results suggest that the long term primary culture of cortical neurons represent a valuable model of neurodegeneration, such as Alzheimer's disease.

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Procaspase-3 and Poly(ADP)ribose Polymerase (PARP) Are Calpain Substrates

Cited by 170 publications

References 31 publications

Constitutive proteasome-mediated turnover of Bfl-1/A1 and its processing in response to TNF receptor activation in FL5.12 pro-B cells convert it into a prodeath factor

Constitutive proteasome-mediated turnover of Bfl-1/A1 and its processing in response to TNF receptor activation in FL5.12 pro-B cells convert it into a prodeath factor

Multiple death pathways in retina-derived 661W cells following growth factor deprivation: crosstalk between caspases and calpains

Neuronal loss in primary long-term cortical culture involves neurodegeneration-like cell death via calpain and p35 processing, but not developmental apoptosis or aging

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