The Jekyll and Hyde Functions of Caspases

Yi, Caroline H.; Yuan, Junying

doi:10.1016/j.devcel.2008.12.012

Cited by 176 publications

(129 citation statements)

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“…In addition to the various mechanisms that regulate caspases during apoptosis, many studies have shown that active caspases play important roles in nonapoptotic cellular functions, including inflammation, protein secretion, and differentiation (reviewed in Kuranaga and Miura 2007;Li and Yuan 2008;Feinstein-Rotkopf and Arama 2009;Yi and Yuan 2009). Caspase activity in the absence of a cell death signal may have unintended deadly consequences in the absence of finely tuned regulation.…”

Section: Caspase Regulation In Nonapoptotic Cellular Processesmentioning

confidence: 99%

Cellular Mechanisms Controlling Caspase Activation and Function

Parrish

Freel

Kornbluth

2013

Cold Spring Harbor Perspectives in Biology

512

383

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Caspases are the primary drivers of apoptotic cell death, cleaving cellular proteins that are critical for dismantling the dying cell. Initially translated as inactive zymogenic precursors, caspases are activated in response to a variety of cell death stimuli. In addition to factors required for their direct activation (e.g., dimerizing adaptor proteins in the case of initiator caspases that lie at the apex of apoptotic signaling cascades), caspases are regulated by a variety of cellular factors in a myriad of physiological and pathological settings. For example, caspases may be modified posttranslationally (e.g., by phosphorylation or ubiquitylation) or through interaction of modulatory factors with either the zymogenic or active form of a caspase, altering its activation and/or activity. These regulatory events may inhibit or enhance enzymatic activity or may affect activity toward particular cellular substrates. Finally, there is emerging literature to suggest that caspases can participate in a variety of cellular processes unrelated to apoptotic cell death. In these settings, it is particularly important that caspases are maintained under stringent control to avoid inadvertent cell death. It is likely that continued examination of these processes will reveal new mechanisms of caspase regulation with implications well beyond control of apoptotic cell death.

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Section: Caspase Regulation In Nonapoptotic Cellular Processesmentioning

confidence: 99%

Cellular Mechanisms Controlling Caspase Activation and Function

Parrish

Freel

Kornbluth

2013

Cold Spring Harbor Perspectives in Biology

512

383

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“…We focused on caspase 3, the major apoptotic effector enzyme that acts in conjunction with initiator caspases 8 and 9, which are involved in alternate apoptotic pathways and in some cases cell activation. 31 To quantify caspase activity, we used a fluorescently conjugated caspase-specific substrate that can be combined with cell-surface staining to compare apoptotic activity between the GC and This suggests that reduced apoptosis may be contributing to the phenotypic differences observed between WT and AID Ϫ/Ϫ GCs. Because antibiotic treatment revealed an immunization-dependent increase in the GC compartment of AID Ϫ/Ϫ mice, we tested caspase activity in these mice as well.…”

Section: Reduced Apoptosis In Aid ؊/؊ Gc B Cellsmentioning

confidence: 99%

“…We focused on caspase 3, the major apoptotic effector enzyme that acts in conjunction with initiator caspases 8 and 9, which are involved in alternate apoptotic pathways and in some cases cell activation. 31 To quantify caspase activity, we used a fluorescently conjugated caspase-specific substrate that can be combined with cell-surface staining to compare apoptotic activity between the GC and For personal use only. on March 28, 2019. by guest www.bloodjournal.org From follicular (ie, background) populations.…”

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confidence: 99%

AID constrains germinal center size by rendering B cells susceptible to apoptosis

Zaheen

Boulianne

Parsa

et al. 2009

Blood

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IntroductionA fundamental hallmark of humoral immunity is the ability to produce class-switched antibodies that have enhanced affinity for antigen. This process, termed affinity maturation, allows clonally selected B cells to refine their response to theoretically target any antigen with high specificity. After activation, B cells mutate the immunoglobulin (Ig) locus in a process known as somatic hypermutation (SHM). 1 Mutated clones that have acquired increased affinity for antigen preferentially expand over their low-affinity counterparts. The selection process occurs in the germinal center (GC), a transient microenvironment that forms in secondary lymphoid tissue shortly after antigen exposure. 2 The GC provides a competitive setting for B cells whereby ineffectual clones are actively cleared from the system via apoptosis, although the processes that govern this selection still remain vague.SHM and class switch recombination (CSR) are initiated by the enzyme activation-induced cytidine deaminase (AID), 3,4 which deaminates cytidines to uridines specifically at the Ig locus. 5-10 AID-generated uridines are then engaged by various DNA repair pathways that either lead to the generation of point mutations in the antibody variable region or recombinogenic events that lead to CSR. AID Ϫ/Ϫ mice lack mutations at their Ig locus and are incapable of producing class-switched antibodies. 4 Interestingly, these mice were previously shown to harbor an abnormally high proportion of splenic GC B cells. 11 This phenotype is also recapitulated in humans with AID deficiencies. 3 Although a link between reduced gut immunity (resulting from an inability to produce mucosal IgA) and peripheral GC formation was hypothesized to account for these abnormalities, this remains to be conclusively proven, and the possibility of a B cell-intrinsic effect that could explain the profound expansion of GC B cells has not been examined.GC B cells represent a unique lymphoid compartment of actively proliferating cells where numerous apoptotic factors must synergize to induce the elimination of nonproductive clones. Factors contributing to the intrinsic pathway of apoptosis, such as Bcl-2, Bcl-x L , and Bim, 12-17 and the extrinsic pathway, such as Fas, [18][19][20][21][22] have been implicated in GC selection. The unique physiology of these cells makes them highly susceptible to disease progression, often serving as etiologic sites for autoimmune and malignant B cells. 13,[23][24][25][26] Recent evidence has implicated AID as a fundamental contributor to the genetic aberrations that lead to these disease phenotypes. 24,[27][28][29] Given the importance of apoptosis as a parameter for both GC B-cell selection and lymphomagenesis, we investigated the relationship between AID-induced DNA mutation and cell death to understand how this enzyme may impinge on survival and death within the GC niche. Here we report that many of the potentially harmful AID-induced genetic alterations may indeed lead to the death of these cells within the GC. Methods Mice...

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“…Antiapoptotic control relies on antiapoptotic proteins activation (Bcl 2, Bcl XL) and IAPs (c-IAP-1, SURVIVIN, LIVIN, XIAP, etc.) (4,10). There are certain proteins in the cell that inhibit initiator caspases, but IAPs are the only known endogenous proteins that regulate the activity of both initiator and effector caspases (11).…”

Section: Function and Inhibition Of Caspasesmentioning

confidence: 99%

Apoptosis Regulation by Inhibitors of Programmed Cell Death

Marković¹,

Đorđević²

2013

Journal of Medical Biochemistry

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Summary: Apoptosis is a form of cell death which is important in many physiological processes. Four apoptotic mechanisms have been identified but two have been well examined: the intrinsic and the extrinsic mechanism. Due to many pro/antiapoptotic factors, these processes take place on a physiologically useful level. In cases of apoptosis dysregu lation, illnesses occur such as neurodegenerative diseases combined with an increased level of cell death or cancerogenesis associated with uncontrolled cell proliferation. Apoptosis can be triggered by the activation of the first caspase in a series and stopped by its deactivation, which represents a new challenge: determining the »point of no return«. Besides the antiapoptotic proteins (Bcl 2, Bcl XL), a family of proteins called the Inhibitors of Apoptosis Proteins (IAPs) play a key role in the regulation of apoptosis. Members of the IAP family are: cIAP1, cIAP2, XIAP, Survivin, Livin and TsIAP. Domain BIR is the most important in the IAP structure since it determines their specificity for caspases. The interaction of IAPs with caspases is complex and not completely understood, however, IAPs are considered to be important target proteins in the therapy of tumor and autoimmune diseases. Keywords: IAP protein (apoptosis), caspases, programmed cell death type IKratak sadr`aj: Apoptoza predstavlja oblik }elijske smrti i va`na je u mnogim fiziolo{kim procesima. Postojẽ etiri oblika }elijske smrti a dva su dobro prou~ena: unutra{nji i spolja{nji. Zahvaljuju}i mnogim pro/antiapoptoti~kim faktorima, ovaj proces se odvija na fiziolo{ki korisnom nivou. U slu~aju disregulacije apoptoze nastaju bolesti kao {to su neurodegenerativna oboljenja udru`ena sa povi{enim nivoom }elijske smrti ili karcinogeneza udru`ena sa nekontrolisanom }elijskom proliferacijom. Apoptozu mo`e po krenuti aktivacija prve kaspaze u nizu i prekinuti njena deaktivacija, {to predstavlja novi izazov: odrediti »ta~ku bez povratka«. Pored antiapoptoti~nih proteina (Bcl 2, Bcl XL), familija proteina nazvanih inhibitori apoptoze (eng. Inhibitors of Apoptosis Proteins, IAPs) igra klju~nu ulogu u procesu regulacije. Pripadnici familije IAP su: cIAP1, cIAP2, XIAP, survivin, livin i TsIAP. Domen BIR je naj zna~ajniji u strukturi IAP budu}i da odre|uje specifi~nost ka kaspazama. Interakcija IAP sa kaspazama je kompleksna i nedovoljno istra`ena, me|utim, smatra se da IAPs pred stavljaju va`ne ciljne proteine u terapiji tumora i auto imunih oboljenja.

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The Jekyll and Hyde Functions of Caspases

Cited by 176 publications

References 123 publications

Cellular Mechanisms Controlling Caspase Activation and Function

Cellular Mechanisms Controlling Caspase Activation and Function

AID constrains germinal center size by rendering B cells susceptible to apoptosis

Apoptosis Regulation by Inhibitors of Programmed Cell Death

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