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ABSTRACT: Members of the conserved small heat shock protein (sHSP) family, such as αB-crystallin and Hsp27, are constitutively expressed in diverse malignancies and have been linked to several hallmark features of cancer including apoptosis resistance. In contrast, the sHSP HspB2/MKBP, which shares an intergenic promoter with αB-crystallin, was discovered as a chaperone of the myotonic dystrophy protein kinase and has not been previously implicated in apoptosis regulation. Here we describe a new function for HspB2 as a novel inhibitor of apical caspase activation in the extrinsic apoptotic pathway. Specifically, we demonstrate that HspB2 is expressed in a subset of human breast cancer cell lines and that ectopic expression of HspB2 in breast cancer cells confers resistance to apoptosis induced by both TRAIL and TNF-α. We also show that HspB2 inhibits the extrinsic apoptotic pathway by suppressing apical caspases-8 and 10 activation, thereby blocking downstream apoptotic events, such as Bid cleavage and caspase-3 activation. Consistent with these in vitro effects, HspB2 attenuates the anti-tumor activity of TRAIL in an orthotopic xenograft model of breast cancer. Collectively, our results reveal a novel function of HspB2 as an anti-apoptotic protein that negatively regulates apical caspase activation in the extrinsic apoptotic pathway.
Breast Cancer Research and Treatment 11/2010; 124(2):307-15. · 4.43 Impact Factor
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ABSTRACT: Human epidermal growth factor receptor-2 (HER-2/ErbB2/neu), a receptor tyrosine kinase that is amplified/overexpressed in poor prognosis breast carcinomas, confers resistance to apoptosis by activating cell survival pathways. Here we demonstrate that the cytoplasmic tail of HER-2 is cleaved by caspases at Asp(1016)/Asp(1019) to release a approximately 47-kDa product, which is subsequently proteolyzed by caspases at Asp(1125) into an unstable 22-kDa fragment that is degraded by the proteasome and a predicted 25-kDa product. Both the 47- and 25-kDa products translocate to mitochondria, release cytochrome c by a Bcl-x(L)-suppressible mechanism, and induce caspase-dependent apoptosis. The 47- and 25-kDa HER-2 cleavage products share a functional BH3-like domain, which is required for cytochrome c release in cells and isolated mitochondria and for apoptosis induction. Caspase-cleaved HER-2 binds Bcl-x(L) and acts synergistically with truncated Bid to induce apoptosis, mimicking the actions of the BH3-only protein Bad. Moreover, the HER-2 cleavage products cooperate with Noxa to induce apoptosis in cells expressing both Bcl-x(L) and Mcl-1, confirming their Bad-like function. Collectively, our results indicate that caspases activate a previously unrecognized proapoptotic function of HER-2 by releasing a Bad-like cell death effector.
Journal of Biological Chemistry 07/2008; 283(26):18269-82. · 4.77 Impact Factor
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ABSTRACT: Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic antibodies targeting its receptors are promising cancer therapies because of their tumor selectivity, many tumors are resistant to TRAIL-based therapies. We examined whether the nonsteroidal anti-inflammatory drug aspirin sensitized cancer cells to TRAIL agonists in vitro and in vivo and investigated the underlying mechanism.
The effects of aspirin on sensitivity to TRAIL agonists and expression of apoptosis regulators was determined in human breast cancer cell lines and xenograft tumors. The specific role of survivin depletion in the TRAIL-sensitizing effects of aspirin was determined by silencing survivin.
Aspirin sensitized human breast cancer cells, but not untransformed human mammary epithelial cells, to TRAIL-induced caspase activation and apoptosis by a cyclooxygenase-2-independent mechanism. Aspirin also sensitized breast cancer cells to apoptosis induced by a human agonistic TRAIL receptor-2 monoclonal antibody (lexatumumab). Aspirin treatment led to G1 cell cycle arrest and a robust reduction in the levels of the antiapoptotic protein survivin by inducing its proteasomal degradation, but did not affect the levels of many other apoptosis regulators. Silencing survivin with small interfering RNAs sensitized breast cancer cells to TRAIL-induced apoptosis, underscoring the functional role of survivin depletion in the TRAIL-sensitizing actions of aspirin. Moreover, aspirin acted synergistically with TRAIL to promote apoptosis and reduce tumor burden in an orthotopic breast cancer xenograft model.
Aspirin sensitizes transformed breast epithelial cells to TRAIL-based therapies in vitro and in vivo by a novel mechanism involving survivin depletion. These findings provide the first in vivo evidence for the therapeutic utility of this combination.
Clinical Cancer Research 06/2008; 14(10):3168-76. · 7.74 Impact Factor
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ABSTRACT: Basal-like tumors are a newly recognized estrogen receptor (ER) negative and HER2 negative breast cancer subtype that express basal epithelial genes and are associated with poor survival. Metaplastic carcinomas are thought to belong within the basal-like group. We have recently demonstrated that the small heat shock protein alphaB-crystallin is commonly expressed in basal-like tumors and contributes to their aggressive phenotype. The current study examined the rates and patterns of alphaB-crystallin expression in whole tissue sections of human breast, including normal tissue, proliferative lesions, in situ and invasive carcinomas (ER positive, HER2 positive, basal-like, and metaplastic cancers). In normal breast tissue, proliferative lesions and in situ carcinomas, alphaB-crystallin expression was restricted to the myoepithelial cell compartment of ductal and lobular units. Most basal-like and metaplastic carcinomas demonstrated cytoplasmic expression of alphaB-crystallin (81% and 86%, respectively). Conversely, no staining for alphaB-crystallin was observed in nonbasal-like (ie, ER positive or HER2 positive) breast carcinomas. Taken together, our results indicate that alphaB-crystallin is a sensitive (81%) and specific (100%) marker for basal-like breast carcinomas. Moreover, the high rates of expression of alphaB-crystallin in metaplastic breast carcinomas (86%) suggest that these tumors may represent a histologically distinctive subset of basal-like breast tumors with a similar underlying molecular etiology.
Annals of Diagnostic Pathology 03/2008; 12(1):33-40. · 0.88 Impact Factor
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Olga Ivanov, Feng Chen,
Elizabeth L Wiley,
Anjeni Keswani,
Leslie K Diaz,
Heidi C Memmel,
Alfred Rademaker,
William J Gradishar,
Monica Morrow,
Seema A Khan,
Vincent L Cryns
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ABSTRACT: alphaB-crystallin is an anti-apoptotic protein commonly expressed in poor prognosis basal-like breast tumors, which are largely triple (estrogen receptor (ER), progesterone receptor (PR), and HER2) negative. We examined whether alphaB-crystallin expression in breast cancer was associated with a poor response to neoadjuvant (preoperative) chemotherapy.
One hundred and twelve breast cancer patients who received neoadjuvant chemotherapy and who had post-chemotherapy tumor specimens available for analysis were included in the study. Forty-nine percent of patients were treated with doxorubicin and cyclophosphamide (AC), 37% received AC in combination with a taxane, and 14% received other regimens. Paired pre- and post-chemotherapy tumor specimens were available for 33 patients. alphaB-crystallin expression was determined by immunohistochemistry in tissue microarrays.
Seventeen percent of tumors were alphaB-crystallin positive. alphaB-crystallin expression was identical in 32 of 33 cases for which both pre- and post-chemotherapy tumor tissue was available. alphaB-crystallin expression was associated with ER-negative (P = 0.0024) and triple negative status (P = 0.005). Overall response rates (ORR) defined as > or =50% reduction in tumor size after treatment were 53% (clinical ORR) and 61% (pathological ORR). Although tumor grade, size, ER, PR, HER2 or triple negative status was not associated with response, alphaB-crystallin-positive tumors had poorer overall response rates than alphaB-crystallin-negative tumors (clinical ORR, 21% vs. 59%, respectively, P = 0.0045; pathological ORR, 16% vs. 70%, respectively, P < 0.0001).
alphaB-crystallin is a novel biomarker expressed predominantly in triple negative breast tumors that identifies a subset of chemotherapy-resistant tumors, which may contribute to their poor prognosis.
Breast Cancer Research and Treatment 10/2007; 111(3):411-7. · 4.43 Impact Factor
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ABSTRACT: The armadillo family protein plakoglobin (Pg) is a well-characterized component of anchoring junctions, where it functions to mediate cell-cell adhesion and maintain epithelial tissue integrity. Although its closest homolog beta-catenin acts in the Wnt signaling pathway to dictate cell fate and promote proliferation and survival, the role of Pg in these processes is not well understood. Here, we investigate how Pg affects the survival of mouse keratinocytes by challenging both Pg-null cells and their heterozygote counterparts with apoptotic stimuli. Our results indicate that Pg deletion protects keratinocytes from apoptosis, with null cells exhibiting delayed mitochondrial cytochrome c release and activation of caspase-3. Pg-null keratinocytes also exhibit increased messenger RNA and protein levels of the anti-apoptotic molecule Bcl-X(L) compared to heterozygote controls. Importantly, reintroduction of Pg into the null cells shifts their phenotype towards that of the Pg+/- keratinocytes, providing further evidence that Pg plays a direct role in regulating cell survival. Taken together, our results suggest that in addition to its adhesive role in epithelia, Pg may also function in contrast to the pro-survival tendencies of beta-catenin, to potentiate death in cells damaged by apoptotic stimuli, perhaps limiting the potential for the propagation of mutations and cellular transformation.
Journal of Investigative Dermatology 05/2007; 127(4):792-801. · 6.31 Impact Factor
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ABSTRACT: Caspases are a conserved family of cell death proteases that cleave intracellular substrates at Asp residues to modify their function and promote apoptosis. In this report we identify the integrin beta4 subunit as a novel caspase substrate using an expression cloning strategy. Together with its alpha6 partner, alpha6beta4 integrin anchors epithelial cells to the basement membrane at specialized adhesive structures known as hemidesmosomes and plays a critical role in diverse epithelial cell functions including cell survival and migration. We show that integrin beta4 is cleaved by caspase-3 and -7 at a conserved Asp residue (Asp(1109)) in vitro and in epithelial cells undergoing apoptosis, resulting in the removal of most of its cytoplasmic tail. Caspase cleavage of integrin beta4 produces two products, 1) a carboxyl-terminal product that is unstable and rapidly degraded by the proteasome and 2) an amino-terminal cleavage product (amino acids 1-1109) that is unable to assemble into mature hemidesmosomes. We also demonstrate that caspase cleavage of integrin beta4 sensitizes epithelial cells to apoptosis and inhibits cell migration. Taken together, we have identified a previously unrecognized proteolytic truncation of integrin beta4 generated by caspases that disrupts key structural and functional properties of epithelial cells and promotes apoptosis.
Journal of Biological Chemistry 03/2007; 282(8):5560-9. · 4.77 Impact Factor
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ABSTRACT: Although a number of cell adhesion proteins have been identified as caspase substrates, the potential role of differentiation-specific desmosomal cadherins during apoptosis has not been examined. Here, we demonstrate that UV-induced caspase cleavage of the human desmoglein 1 cytoplasmic tail results in distinct 17- and 140- kDa products, whereas metalloproteinase-dependent shedding of the extracellular adhesion domain generates a 75-kDa product. In vitro studies identify caspase-3 as the preferred enzyme that cleaves desmoglein 1 within its unique repeating unit domain at aspartic acid 888, part of a consensus sequence not conserved among the other desmosomal cadherins. Apoptotic processing leads to decreased cell surface expression of desmoglein 1 and re-localization of its C terminus diffusely throughout the cytoplasm over a time course comparable with the processing of other desmosomal proteins and cytoplasmic keratins. Importantly, whereas classic cadherins have been reported to promote cell survival, short hairpin RNA-mediated suppression of desmoglein 1 in differentiated keratinocytes protected cells from UV-induced apoptosis. Collectively, our results identify desmoglein 1 as a novel caspase and metalloproteinase substrate whose cleavage likely contributes to the dismantling of desmosomes during keratinocyte apoptosis and also reveal desmoglein 1 as a previously unrecognized regulator of apoptosis in keratinocytes.
Journal of Biological Chemistry 03/2006; 281(6):3614-24. · 4.77 Impact Factor
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Jose V Moyano,
Joseph R Evans, Feng Chen,
Meiling Lu,
Michael E Werner,
Fruma Yehiely,
Leslie K Diaz,
Dmitry Turbin,
Gamze Karaca,
Elizabeth Wiley,
Torsten O Nielsen,
Charles M Perou,
Vincent L Cryns
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ABSTRACT: Recent gene profiling studies have identified a new breast cancer subtype, the basal-like group, which expresses genes characteristic of basal epithelial cells and is associated with poor clinical outcomes. However, the genes responsible for the aggressive behavior observed in this group are largely unknown. Here we report that the small heat shock protein alpha-basic-crystallin (alphaB-crystallin) was commonly expressed in basal-like tumors and predicted poor survival in breast cancer patients independently of other prognostic markers. We also demonstrate that overexpression of alphaB-crystallin transformed immortalized human mammary epithelial cells (MECs). In 3D basement membrane culture, alphaB-crystallin overexpression induced luminal filling and other neoplastic-like changes in mammary acini, while silencing alphaB-crystallin by RNA interference inhibited these abnormalities. alphaB-Crystallin overexpression also induced EGF- and anchorage-independent growth, increased cell migration and invasion, and constitutively activated the MAPK kinase/ERK (MEK/ERK) pathway. Moreover, the transformed phenotype conferred by alphaB-crystallin was suppressed by MEK inhibitors. In addition, immortalized human MECs overexpressing alphaB-crystallin formed invasive mammary carcinomas in nude mice that recapitulated aspects of human basal-like breast tumors. Collectively, our results indicate that alphaB-crystallin is a novel oncoprotein expressed in basal-like breast carcinomas that independently predicts shorter survival. Our data also implicate the MEK/ERK pathway as a potential therapeutic target for these tumors.
Journal of Clinical Investigation 02/2006; 116(1):261-70. · 15.39 Impact Factor
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Merideth C Kamradt,
Meiling Lu,
Michael E Werner,
Toni Kwan, Feng Chen,
Anne Strohecker,
Shayna Oshita,
John C Wilkinson,
Chunjiang Yu,
Patsy G Oliver,
Colin S Duckett,
Donald J Buchsbaum,
Albert F LoBuglio,
V Craig Jordan,
Vincent L Cryns
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ABSTRACT: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor alpha family of cytokines that preferentially induces apoptosis in transformed cells, making it a promising cancer therapy. However, many neoplasms are resistant to TRAIL-induced apoptosis by mechanisms that are poorly understood. We demonstrate that the expression of the small heat shock protein alpha B-crystallin (but not other heat shock proteins or apoptosis-regulating proteins) correlates with TRAIL resistance in a panel of human cancer cell lines. Stable expression of wild-type alpha B-crystallin, but not a pseudophosphorylation mutant impaired in its assembly and chaperone function, protects cancer cells from TRAIL-induced caspase-3 activation and apoptosis in vitro. Furthermore, selective inhibition of alpha B-crystallin expression by RNA interference sensitizes cancer cells to TRAIL. In addition, wild-type alpha B-crystallin promotes xenograft tumor growth and inhibits TRAIL-induced apoptosis in vivo in nude mice, whereas a pseudophosphorylation alpha B-crystallin mutant impaired in its anti-apoptotic function inhibits xenograft tumor growth. Collectively, these findings indicate that alpha B-crystallin is a novel regulator of TRAIL-induced apoptosis and tumor growth. Moreover, these results demonstrate that targeted inhibition of alpha B-crystallin promotes TRAIL-induced apoptosis, thereby suggesting a novel strategy to overcome TRAIL resistance in cancer.
Journal of Biological Chemistry 04/2005; 280(12):11059-66. · 4.77 Impact Factor
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ABSTRACT: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapy that preferentially induces apoptosis in cancer cells. However, many neoplasms are resistant to TRAIL by mechanisms that are poorly understood. Here we demonstrate that human breast cancer cells, but not normal mammary epithelial cells, are dramatically sensitized to TRAIL-induced apoptosis and caspase activation by peroxisome proliferator-activated receptor gamma (PPARgamma) agonists of the thiazolidinedione (TZD) class. Although TZDs do not significantly alter the expression of components of the TRAIL signaling pathway, they profoundly reduce protein levels of cyclin D3, but not other D-type cyclins, by decreasing cyclin D3 mRNA levels and by inducing its proteasomal degradation. Importantly, both TRAIL sensitization and reduction in cyclin D3 protein levels induced by TZDs are likely PPARgamma-independent because a dominant negative mutant of PPARgamma did not antagonize these effects of TZDs, nor were they affected by the expression levels of PPARgamma. TZDs also inhibit G(1) to S cell cycle progression. Furthermore, silencing cyclin D3 by RNA interference inhibits S phase entry and sensitizes breast cancer cells to TRAIL, indicating a key role for cyclin D3 repression in these events. G(1) cell cycle arrest sensitizes breast cancer cells to TRAIL at least in part by reducing levels of the anti-apoptotic protein survivin: ectopic expression of survivin partially suppresses apoptosis induced by TRAIL and TZDs. We also demonstrate for the first time that TZDs promote TRAIL-induced apoptosis of breast cancer in vivo, suggesting that this combination may be an effective therapy for cancer.
Journal of Biological Chemistry 03/2005; 280(8):6742-51. · 4.77 Impact Factor
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ABSTRACT: Caspases are critical proapoptotic proteases that execute cell death signals by selectively cleaving proteins at Asp residues to alter their function. Caspases trigger apoptotic chromatin degradation by activating caspase-activated DNase and by inactivating a number of enzymes that sense or repair DNA damage. We have identified the mismatch repair protein MLH1 as a novel caspase-3 substrate by screening small pools of a human prostate adenocarcinoma cDNA library for cDNAs encoding caspase substrates. In this report, we demonstrate that human MLH1 is specifically cleaved by caspase-3 at Asp(418) in vitro. Furthermore, MLH1 is rapidly proteolyzed by caspase-3 in cancer cells induced to undergo apoptosis by treatment with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the topoisomerase II inhibitor etoposide, which damages DNA. Importantly, proteolysis of MLH1 by caspase-3 triggers its partial redistribution from the nucleus to the cytoplasm and generates a proapoptotic carboxyl-terminal product. In addition, we demonstrate that a caspase-3 cleavage-resistant D418E MLH1 mutant inhibits etoposide-induced apoptosis but has little effect on TRAIL-induced apoptosis. These results indicate that the proteolysis of MLH1 by caspase-3 plays a functionally important and previously unrecognized role in the execution of DNA damage-induced apoptosis.
Journal of Biological Chemistry 07/2004; 279(26):27542-8. · 4.77 Impact Factor
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T Chris Gamblin, Feng Chen,
Angara Zambrano,
Aida Abraha,
Sarita Lagalwar,
Angela L Guillozet,
Meiling Lu,
Yifan Fu,
Francisco Garcia-Sierra,
Nichole LaPointe,
Richard Miller,
Robert W Berry,
Lester I Binder,
Vincent L Cryns
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ABSTRACT: The principal pathological features of Alzheimer's disease (AD) are extracellular amyloid plaques and intracellular neurofibrillary tangles, the latter composed of the microtubule-binding protein tau assembled into paired helical and straight filaments. Recent studies suggest that these pathological entities may be functionally linked, although the mechanisms by which amyloid deposition promotes pathological tau filament assembly are poorly understood. Here, we report that tau is proteolyzed by multiple caspases at a highly conserved aspartate residue (Asp421) in its C terminus in vitro and in neurons treated with amyloid-beta (Abeta) (1-42) peptide. Tau is rapidly cleaved at Asp421 in Abeta-treated neurons (within 2 h), and its proteolysis appears to precede the nuclear events of apoptosis. We also demonstrate that caspase cleavage of tau generates a truncated protein that lacks its C-terminal 20 amino acids and assembles more rapidly and more extensively into tau filaments in vitro than wild-type tau. Using a monoclonal antibody that specifically recognizes tau truncated at Asp421, we show that tau is proteolytically cleaved at this site in the fibrillar pathologies of AD brain. Taken together, our results suggest a novel mechanism linking amyloid deposition and neurofibrillary tangles in AD: Abeta peptides promote pathological tau filament assembly in neurons by triggering caspase cleavage of tau and generating a proteolytic product with enhanced polymerization kinetics.
Proceedings of the National Academy of Sciences 09/2003; 100(17):10032-7. · 9.68 Impact Factor
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ABSTRACT: Caspase cleavage of key cytoskeletal proteins, including several intermediate filament proteins, triggers the dramatic disassembly of the cytoskeleton that characterizes apoptosis. Here we describe the muscle-specific intermediate filament protein desmin as a novel caspase substrate. Desmin is cleaved selectively at a conserved Asp residue in its L1-L2 linker domain (VEMD downward arrow M(264)) by caspase-6 in vitro and in myogenic cells undergoing apoptosis. We demonstrate that caspase cleavage of desmin at Asp(263) has important functional consequences, including the production of an amino-terminal cleavage product, N-desmin, which is unable to assemble into intermediate filaments, instead forming large intracellular aggregates. Moreover, N-desmin functions as a dominant-negative inhibitor of filament assembly, both for desmin and the structurally related intermediate filament protein vimentin. We also show that stable expression of a caspase cleavage-resistant desmin D263E mutant partially protects cells from tumor necrosis factor-alpha-induced apoptosis. Taken together, these results indicate that caspase proteolysis of desmin at Asp(263) produces a dominant-negative inhibitor of intermediate filaments and actively participates in the execution of apoptosis. In addition, these findings provide further evidence that the intermediate filament cytoskeleton has been targeted systematically for degradation during apoptosis.
Journal of Biological Chemistry 03/2003; 278(9):6848-53. · 4.77 Impact Factor
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ABSTRACT: Myoblasts respond to growth factor deprivation either by differentiating into multinucleated myotubes or by undergoing apoptosis; hence, the acquisition of apoptosis resistance by myogenic precursors is essential for their development. Here we demonstrate that the expression of the small heat shock protein alpha B-crystallin is selectively induced in C2C12 myoblasts that are resistant to differentiation-induced apoptosis, and we show that this induction occurs at an early stage in their differentiation in vitro. In contrast, the expression of several known anti-apoptotic proteins (FLIP, XIAP, Bcl-x(L)) was not altered during myogenesis. We also demonstrate that ectopic expression of alpha B-crystallin, but not the closely related small heat shock protein Hsp27, renders C2C12 myoblasts resistant to differentiation-induced apoptosis. Furthermore, we show that the myopathy-causing R120G alpha B-crystallin mutant is partly impaired in its cytoprotective function, whereas a pseudophosphorylation alpha B-crystallin mutant that mimics stress-induced phosphorylation is completely devoid of anti-apoptotic activity. Finally, we demonstrate that alpha B-crystallin negatively regulates apoptosis during myogenesis by inhibiting the proteolytic activation of caspase-3, whereas the R120G and pseudophosphorylation mutants are defective in this function. Taken together, our findings indicate that alpha B-crystallin is a novel negative regulator of myogenic apoptosis that directly links the differentiation program to apoptosis resistance.
Journal of Biological Chemistry 11/2002; 277(41):38731-6. · 4.77 Impact Factor
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ABSTRACT: Caspases are a conserved family of proteases that play a critical role in the execution of apoptosis by cleaving key cellular proteins at Asp residues and modifying their function. Using an expression cloning strategy we recently developed, we isolated human RAD21/SCC1/MCD1 as a novel caspase substrate. RAD21 is a component of the cohesin complex that holds sister chromatids together during mitosis and repairs double-strand DNA breaks. Interestingly, RAD21 is cleaved by a caspase-like Esp1/separase at the onset of anaphase to trigger sister chromatid separation. Here, we demonstrate that human RAD21 is preferentially cleaved at Asp(279) by caspases-3 and -7 in vitro to generate two major proteolytic products of approximately 65 and 48 kDa. Moreover, we show that RAD21 is specifically proteolyzed by caspases into a similarly sized 65-kDa carboxyl-terminal product in cells undergoing apoptosis in response to diverse stimuli. We also demonstrate that caspase proteolysis of RAD21 precedes apoptotic chromatin condensation and has important functional consequences, viz. the partial removal of RAD21 from chromatin and the production of a proapoptotic carboxyl-terminal cleavage product that amplifies the cell death signal. Taken together, these findings point to an entirely novel function of RAD21 in the execution of apoptosis.
Journal of Biological Chemistry 06/2002; 277(19):16775-81. · 4.77 Impact Factor
