The sensitivity of c-Jun and c-Fos proteins to calpains depends on conformational determinants of the monomers and not on formation of dimers

Pariat, Magali; Salvat, Catherine; Bébien, Magali; Brockly, Frédérique; Altieri, Eléna; Carillo, Serge; Jariel-Encontre, Isabelle; Piechaczyk, Marc

doi:10.1042/bj3450129

Cited by 34 publications

(13 citation statements)

References 30 publications

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“…The concept that the calpains are involved in regulation of gene expression seems to be based to a considerable extent on ability of the calpains to cleave several transcription factors such as c-Jun, c-Fos (166,341), and p53 (141,216,340) in in vitro assays. These same transcription factors are also degraded by the proteasome, however, and it seems likely that the proteasome is the principal route of degradation of these transcription factors in cells.…”

Section: Regulation Of Gene Expressionmentioning

confidence: 99%

The Calpain System

Goll

Thompson

et al. 2003

Physiological Reviews

2,571

2,801

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Goll, Darrel E., Valery F. Thompson, Hongqi Li, Wei Wei, and Jinyang Cong. The Calpain System. Physiol Rev 83: 731–801, 2003; 10.1152/physrev.00029.2002.—The calpain system originally comprised three molecules: two Ca2+-dependent proteases, μ-calpain and m-calpain, and a third polypeptide, calpastatin, whose only known function is to inhibit the two calpains. Both μ- and m-calpain are heterodimers containing an identical 28-kDa subunit and an 80-kDa subunit that shares 55–65% sequence homology between the two proteases. The crystallographic structure of m-calpain reveals six “domains” in the 80-kDa subunit: 1) a 19-amino acid NH2-terminal sequence; 2) and 3) two domains that constitute the active site, IIa and IIb; 4) domain III; 5) an 18-amino acid extended sequence linking domain III to domain IV; and 6) domain IV, which resembles the penta EF-hand family of polypeptides. The single calpastatin gene can produce eight or more calpastatin polypeptides ranging from 17 to 85 kDa by use of different promoters and alternative splicing events. The physiological significance of these different calpastatins is unclear, although all bind to three different places on the calpain molecule; binding to at least two of the sites is Ca2+ dependent. Since 1989, cDNA cloning has identified 12 additional mRNAs in mammals that encode polypeptides homologous to domains IIa and IIb of the 80-kDa subunit of μ- and m-calpain, and calpain-like mRNAs have been identified in other organisms. The molecules encoded by these mRNAs have not been isolated, so little is known about their properties. How calpain activity is regulated in cells is still unclear, but the calpains ostensibly participate in a variety of cellular processes including remodeling of cytoskeletal/membrane attachments, different signal transduction pathways, and apoptosis. Deregulated calpain activity following loss of Ca2+ homeostasis results in tissue damage in response to events such as myocardial infarcts, stroke, and brain trauma.

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Section: Regulation Of Gene Expressionmentioning

confidence: 99%

The Calpain System

Goll

Thompson

et al. 2003

Physiological Reviews

2,571

2,801

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“…Arg-c-FOS is the Ct fragment of the c-FOS transcriptional regulator. c-FOS is targeted for degradation through more than one degron, including the path that includes the cleavage by calpains 160 and predicted degradation of Arg-c-FOS by the Arg/N-end rule pathway. #20.…”

Section: Monitoring Protein Fragments and Reacting To Their Accumulationmentioning

confidence: 99%

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Varshavsky

2012

Protein Science

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Despite extensive understanding of sleep regulation, the molecular-level cause and function of sleep are unknown. I suggest that they originate in individual neurons and stem from increased production of protein fragments during wakefulness. These fragments are transient parts of protein complexes in which the fragments were generated. Neuronal Ca 21 fluxes are higher during wakefulness than during sleep. Subunits of transmembrane channels and other proteins are cleaved by Ca 21 -activated calpains and by other nonprocessive proteases, including caspases and secretases. In the proposed concept, termed the fragment generation (FG) hypothesis, sleep is a state during which the production of fragments is decreased (owing to lower Ca 21 transients) while fragment-destroying pathways are upregulated. These changes facilitate the elimination of fragments and the remodeling of protein complexes in which the fragments resided. The FG hypothesis posits that a proteolytic cleavage, which produces two fragments, can have both deleterious effects and fitness-increasing functions. This (previously not considered) dichotomy can explain both the conservation of cleavage sites in proteins and the evolutionary persistence of sleep, because sleep would counteract deleterious aspects of protein fragments. The FG hypothesis leads to new explanations of sleep phenomena, including a longer sleep after sleep deprivation. Studies in the 1970s showed that ethanol-induced sleep in mice can be strikingly prolonged by intracerebroventricular injections of either Ca 21 alone or Ca 21 and its ionophore (Erickson et al., Science 1978;199:1219-1221 Harris, Pharmacol Biochem Behav 1979;10:527-534; Erickson et al., Pharmacol Biochem Behav 1980;12:651-656). These results, which were never interpreted in connection to protein fragments or the function of sleep, may be accounted for by the FG hypothesis about molecular causation of sleep.

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“…For instance, calpain is known to degrade IB␣, c-Jun, and c-Fos in vitro, all of which are essential molecular players in osteoclastogenesis (17)(18)(19). Therefore, calpain may play a master role in the regulation of osteoclastogenesis through limited proteolysis of these molecules.…”

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confidence: 99%

μ-Calpain Regulates Receptor Activator of NF-κB Ligand (RANKL)-supported Osteoclastogenesis via NF-κB Activation in RAW 264.7 Cells

Lee

Kim

Karmin

et al. 2005

Journal of Biological Chemistry

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To clarify the role of calpain in the receptor activator of NF-B ligand (RANKL)-supported osteoclastogenesis, RANKL-induced calpain activation was examined by using murine RAW 264.7 cells and bone marrow-derived monocyte/macrophage progenitors. We found that calpain activity increased in response to RANKL in both cell types based on ␣-spectrinolysis and that -calpain, rather than m-calpain, was activated during RANKLsupported osteoclastogenesis in RAW 264.7 cells. Overexpression of -calpain clearly augmented RANKL-supported osteoclastogenesis in RAW 264.7 cells, thereby implicating its pivotal role in this process. Cell-permeable calpain inhibitors, including calpastatin and calpeptin, were sufficient to suppress RANKL-supported osteoclastogenesis based on decreased expression of the osteoclastogenic marker, matrix metalloproteinase 9, and the generation of tartrate-resistant acid phosphatase-positive multinucleated cells in both cell types. Calpain inhibitors suppressed NF-B activation via inhibition of the cleavage of inhibitor of NF-B (IB␣) in RAW 264.7 cells. Taken together, our findings suggest that -calpain is essential to the regulation of RANKL-supported osteoclastogenesis via NF-B activation.

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The sensitivity of c-Jun and c-Fos proteins to calpains depends on conformational determinants of the monomers and not on formation of dimers

Cited by 34 publications

References 30 publications

The Calpain System

The Calpain System

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

μ-Calpain Regulates Receptor Activator of NF-κB Ligand (RANKL)-supported Osteoclastogenesis via NF-κB Activation in RAW 264.7 Cells

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