Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bloom syndrome (BS) is an autosomal recessive disorder characterized by a high incidence of cancer and genomic instability. BLM, the protein defective in BS, is a RECQ-like helicase that is presumed to function in mammalian DNA replication, recombination, or repair. We show here that BLM, but not the related RECQ-like helicase WRN, is rapidly cleaved in cells undergoing apoptosis. BLM was cleaved to 47- and 110-kDa major fragments, with kinetics similar to the apoptotic cleavage of poly(A)DP-ribose polymerase. BLM cleavage was prevented by a caspase 3 inhibitor and did not occur in caspase 3-deficient cells. Moreover, recombinant BLM was cleaved to 47- and 110-kDa fragments by caspase 3, but not caspase 6, in vitro. The caspase 3 recognition sequence (412)TEVD(415) was verified by mutating aspartate 415 to glycine and showing that this mutation rendered BLM resistant to caspase 3 cleavage. Cleavage did not abolish the BLM helicase activity but abolished BLM nuclear foci and the association of BLM with condensed DNA and the insoluble matrix. The results suggest that BLM, but not WRN, is an early selected target during the execution of apoptosis.
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PMID:Selective cleavage of BLM, the bloom syndrome protein, during apoptotic cell death. 3327 4

In higher eukaryotes, the integration of signals triggered in response to certain types of stress can result in programmed cell death. Central to these events is the sequential activation of a cascade of proteinases known as caspases. The final activated effector caspases of this cascade digest a number of cellular proteins, in some cases increasing their enzymatic activity, in others destroying their function. Of the proteins shown to be targets for caspase-mediated proteolysis, a surprisingly large proportion are proteins involved in the signalling or repair of DNA damage. Here we investigate whether BLM, the product of the gene mutated in Bloom's syndrome, a human autosomal disease characterised by cancer predisposition and sunlight sensitivity, is cleaved during apoptosis. BLM interacts with topoisomerase IIIalpha and has been proposed to play an important role in maintaining genomic integrity through its roles in DNA repair and replication. We show that BLM is cleaved during apoptosis by caspase-3 and reveal that the main cleavage site is located at the junction between the N-terminal and central helicase domains of BLM. Proteolytic cleavage by caspase-3 produces a 120 kDa fragment, which contains the intact helicase domain and three smaller fragments, the relative amounts of which depend on time of incubation with caspase-3. The 120 kDa fragment retains the helicase activity of the intact BLM protein. However, its interaction with topoisomerase IIIalpha is severely impaired. Since the BLM-topoisomerase interaction is believed to be necessary for many of the replication and recombination functions of BLM, we suggest that caspase-3 cleavage of BLM could alter the localisation and/or function of BLM and that these changes may be important in the process of apoptosis.
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PMID:Cleavage of the Bloom's syndrome gene product during apoptosis by caspase-3 results in an impaired interaction with topoisomerase IIIalpha. 1147 Aug 74

Oncogenic tyrosine kinases (OTKs) expressed in malignant tumors stimulate cell proliferation, inhibition of apoptosis, and drug resistance. There are at least three mechanisms of response to chemo- and radiotherapy in OTK-positive cells: overexpression of anti-apoptotic proteins (such as Bcl-xL and Bcl-2) and blocking of the activation of pro-apoptotic proteins (such as caspase 3), arrest in the G2/M phase of the cell cycle, and modulation of DNA repair mechanisms. Furthermore, OTKs elevate the level of reactive oxygen species (ROS)-dependent spontaneous DNA damage. The accumulation of mutations in genetic material increases the metastatic potential following further cancer development. Oxidation-damaged DNA bases are repaired primarily via the mechanisms of base excision repair (BER) and nucleotide excision repair (NER). However, during DNA replication, the areas of single-stranded DNA produced by BER and NER can be converted to double-strand breaks (DSBs), which are then repaired via non-homologous end-joining (NHEJ) and homologous recombination repair (HHR) mechanisms. The HHR pathway is activated in OTK-positive cells due to the elevated level of RAD51 protein expression. In addition, RecQ helicases, such as BLM, play a significant role in this process. Understanding the mechanisms activated by OTKs may help in the development of novel therapeutic strategies that use OTKs as a target.
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PMID:[The role of oncogenic tyrosine kinases in the cellular response to anticancer therapy]. 1809 40