Heat shock protein 70 (HSP70) has been shown to act as an inhibitor of apoptosis. We have also observed an inhibitory effect of HSP70 on apoptotic cell death both in preheated U937 and stably transfected HSP70-overexpressing U937 (U937/HSP70) cells. However, the molecular mechanism whereby HSP70 prevents apoptosis still remains to be solved. To address this issue, we investigated the effect of HSP70 on apoptotic processes in an in vitro system. Caspase-3 cleavage and DNA fragmentation were detected in cytosolic fractions from normal cells upon addition of dATP, but not from preheated U937 or U937/hsp70 cells. Moreover, the addition of purified recombinant HSP70 to normal cytosolic fractions prevented caspase-3 cleavage and DNA fragmentation, suggesting that HSP70 prevents apoptosis upstream of caspase-3 processing. Because cytochrome c was still released from mitochondria into the cytosol by lethal heat shock despite prevention of caspase-3 activation and cell death in both preheated U937 and U937/hsp70 cells, it was evident that HSP70 acts downstream of cytochrome c release. Results obtained in vitro with purified deletion mutants of HSP70 showed that the carboxyl one-third region (from amino acids 438 to 641) including the peptide-binding domain and the carboxylterminal EEVD sequence was essential to prevent caspase-3 processing. From these results, we conclude that HSP70 acts as a strong suppressor of apoptosis acting downstream of cytochrome c release and upstream of caspase-3 activation.

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RNA-binding proteins (RBPs) crucially regulate gene expression through post-transcriptional regulation, such as by modulating microRNA (miRNA) processing and the alternative splicing, alternative polyadenylation, subcellular localization, stability, and translation of RNAs. More than 1500 RBPs have been identified to date, and many of them are known to be deregulated in cancer. Alterations in the expression and localization of RBPs can influence the expression levels of oncogenes, tumor-suppressor genes, and genome stability-related genes. RBP-mediated gene regulation can lead to diverse cancer-related cellular phenotypes, such as proliferation, apoptosis, angiogenesis, senescence, and epithelial-mesenchymal transition (EMT)/invasion/metastasis. This regulation can also be associated with cancer prognosis. Thus, RBPs can be potential targets for the development of therapeutics for the cancer treatment. In this review, we describe the molecular functions of RBPs, their roles in cancer-related cellular phenotypes, and various approaches that may be used to target RBPs for cancer treatment.

Background and Purpose-Heat-shock proteins (HSPs) are highly conserved proteins that are induced by a variety of stresses. HSP70 is a 70-kDa HSP family known to have cytoprotective effects against various insults. The role of HSP70 in cerebral ischemia remains to be elucidated in vivo. Methods-To investigate the effect of reduced HSP70 levels on cerebral ischemia, focal cerebral ischemia by intraluminal occlusion of the middle cerebral artery was induced in hsp70.1 knockout mice. The expressions of hsp70.1 and hsp70.3 mRNAs and HSP70 protein were determined, and infarction volumes were measured and compared. Results-Northern blots confirmed the absence of hsp70.1 mRNA expression in the knockout mice. The mean infarction volume was significantly larger in hsp70.1 knockout mice (92.5Ϯ8.3 mm 3 ) than in the wild-type mice (59.3Ϯ8.9 mm,