Nuclear Calpain Regulates Ca2+-dependent Signaling via Proteolysis of Nuclear Ca2+/Calmodulin-dependent Protein Kinase Type IV in Cultured Neurons

Tremper-Wells, Barbara; Vallano, Mary Lou

doi:10.1074/jbc.m410591200

Cited by 59 publications

(43 citation statements)

References 99 publications

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“…There are no reports that SerpinB2 inhibits the proteasome, and it has recently emerged that SerpinB2 inhibits calpain-mediated degradation of Rb. 3 Calpains represent a group of calcium-activated cysteine proteases, two of which, -calpain and m-calpain, are ubiquitously expressed and found both in the cytoplasm and the nucleus (15). Herein we provide evidence that the first step in the E7-mediated degradation of Rb involves calpain cleavage.…”

mentioning

confidence: 72%

Human Papillomavirus E7 Requires the Protease Calpain to Degrade the Retinoblastoma Protein

Darnell

Schroder

Antalis

et al. 2007

Journal of Biological Chemistry

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Cervical cancers transformed by high risk human papilloma virus (HPV) express the E7 oncoprotein, which accelerates the degradation of the retinoblastoma protein (Rb). Here we show that the E7-mediated degradation of Rb requires the calciumactivated cysteine protease, calpain. E7 bound and activated -calpain and promoted cleavage at Rb 810 , with mutation of this residue preventing E7-mediated degradation. The calpain cleavage product, Rb 1-810 , was unable to mediate cell cycle arrest but retained the ability to repress E6/E7 transcription. E7 also promoted the accelerated proteasomal degradation of Infection with high risk human Papillomavirus (HPV)2 types is responsible for virtually all cases of cervical cancer, which is currently the second most common cause of death from cancer among women worldwide (1). Vaccination will likely have a substantial impact; however, current modeling suggests that it may take 40 -50 years to reach an Ϸ50% reduction in mortality (2). Integration of part of the HPV genome is believed to be central to the transformation process (3) and often results in the increased expression of the two viral oncoproteins, E6 and E7. A principle activity of E6 and E7 is promotion of the accelerated degradation of p53 and the retinoblastoma protein (Rb), respectively (4, 5). Hypophosphorylated Rb binds the E2F transcription factor, resulting in repression of E2F-dependent gene transcription and G 1 cell cycle arrest (6). The promotion of Rb degradation mediated by E7 is believed to involve a two-step process (7). First, E7 binds hypophosphorylated Rb (8), which leads to the displacement of E2F and entry into the cell cycle. How E2F is displaced by E7 remains unclear as E7 and E2F binding sites on Rb have recently been shown to be quite distinct (9). The second step involves E7 targeting Rb for accelerated degradation via the proteasome (10 -12). A new insight into the mechanism of E7-mediated degradation of Rb was recently provided by our observation that the serine protease inhibitor SerpinB2 was able to inhibit E7-mediated degradation of Rb in HeLa cells (13,14). There are no reports that SerpinB2 inhibits the proteasome, and it has recently emerged that SerpinB2 inhibits calpain-mediated degradation of Rb. 3Calpains represent a group of calcium-activated cysteine proteases, two of which, -calpain and m-calpain, are ubiquitously expressed and found both in the cytoplasm and the nucleus (15). Herein we provide evidence that the first step in the E7-mediated degradation of Rb involves calpain cleavage. E7 was shown to bind and activate -calpain and promoted cleavage of full-length Rb 1-928 to yield Rb . Rb 1-810 was unable to promote cell cycle arrest, suggesting that this cleavage event was sufficient to displace E2F from Rb. The second step involved the promotion by E7 of the proteasomal degradation of Rb . Calpain inhibitors are being developed for a number of diseases including cancer (16, 17) and were able to inhibit E7-mediated degradation of Rb. They also reduced the viability of HPV-tr...

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mentioning

confidence: 72%

Human Papillomavirus E7 Requires the Protease Calpain to Degrade the Retinoblastoma Protein

Darnell

Schroder

Antalis

et al. 2007

Journal of Biological Chemistry

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“…CAPN2 nuclear localization and activity have been demonstrated in cerebellar granule cells in culture. In granule cells, nuclear activity is associated with selective CaMKIV proteolysis (Tremper-Wells and Vallano, 2005).…”

Section: Sub-cellular Localisation and Differentiation Statusmentioning

confidence: 99%

Calpain 2 expression pattern and sub-cellular localization during mouse embryogenesis

Raynaud¹,

Marcilhac²,

Chébli³

et al. 2008

Int. J. Dev. Biol.

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Regulation of migration and proliferation by calpain has been shown in various cell types; however, no data are available concerning calpain 2 (CAPN2) localization in embryonic tissues. Here, we report the expression pattern of CAPN2 during mouse embryonic development. Expression of the capn2 gene is observed throughout embryonic development. From ES cells and the 8-cell stage to late neurulation stages, CAPN2 is expressed in the cytoplasm and nuclear compartments, with a clear co-localisation with chromatin. Whole-mount in situ hybridization analysis from E8.5 to 14.5 stages indicates high levels of capn2 expression in the nervous system, heart and mesodermal tissues. Up-regulation is maintained during later developmental stages in proliferating cells and in precursor cells involved in muscle (myoblasts) or bone formation (chondrocytes). At later developmental stages, elevated mRNA levels coincided with CAPN2 nuclear localization in these cell types, while differentiated cells maintained cytoplasmic expression. This detailed analysis reveals dynamic expression: nuclear localization was associated either with active cell mitosis in embryonic stem cells and early developmental stages or with precursor cells later during organogenesis. Thus, these data indicate that CAPN2 may represent a key factor in development from the first cell division.

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“…Calpains are cysteine proteases active in the nucleus, cytosol, and extracellular milieu (24)(25)(26). They have been implicated in the pathophysiology of several inflammatory diseases, but calpain activity in IBD or colitis models is not well understood.…”

Section: Il10mentioning

confidence: 99%

Cytosolic HMGB1 controls the cellular autophagy/apoptosis checkpoint during inflammation

Zhu¹,

Messer²,

Wang³

et al. 2015

J. Clin. Invest.

177

134

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Nuclear Calpain Regulates Ca2+-dependent Signaling via Proteolysis of Nuclear Ca2+/Calmodulin-dependent Protein Kinase Type IV in Cultured Neurons

Cited by 59 publications

References 99 publications

Human Papillomavirus E7 Requires the Protease Calpain to Degrade the Retinoblastoma Protein

Human Papillomavirus E7 Requires the Protease Calpain to Degrade the Retinoblastoma Protein

Calpain 2 expression pattern and sub-cellular localization during mouse embryogenesis

Cytosolic HMGB1 controls the cellular autophagy/apoptosis checkpoint during inflammation

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