Hur J, Bell DW, Dean KL, Coser KR, Hilario PC, Okimoto RA et al.. Regulation of expression of BIK proapoptotic protein in human breast cancer cells: p53-dependent induction of BIK mRNA by fulvestrant and proteasomal degradation of BIK protein. Cancer Res 66: 10153-10161
ABSTRACT Induction of mRNA for BIK proapoptotic protein by doxorubicin or gamma-irradiation requires the DNA-binding transcription factor activity of p53. In MCF7 cells, pure antiestrogen fulvestrant also induces BIK mRNA and apoptosis. Here, we provide evidence that, in contrast to doxorubicin or gamma-irradiation, fulvestrant induction of BIK mRNA is not a direct effect of the transcriptional activity of p53, although p53 is necessary for this induction. It is known that p53 up-regulated modulator of apoptosis (PUMA) mRNA is induced directly by the transcriptional activity of p53. Whereas gamma-irradiation induced both BIK and PUMA mRNA, only BIK mRNA was induced by fulvestrant. Whereas both fulvestrant and doxorubicin induced BIK mRNA, only doxorubicin enhanced the DNA-binding activity of p53 and induced PUMA mRNA. Small interfering RNA (siRNA) suppression of p53 expression as well as overexpression of dominant-negative p53 effectively inhibited the fulvestrant induction of BIK mRNA, protein, and apoptosis. Transcriptional activity of a 2-kb BIK promoter, which contained an incomplete p53-binding sequence, was not affected by fulvestrant when tested by reporter assay. Fulvestrant neither affected the stability of the BIK mRNA transcripts. Interestingly, other human breast cancer cells, such as ZR75-1, constitutively expressed BIK mRNA even without fulvestrant. In these cells, however, BIK protein seemed to be rapidly degraded by proteasome, and siRNA suppression of BIK in ZR75-1 cells inhibited apoptosis induced by MG132 proteasome inhibitor. These results suggest that expression of BIK in human breast cancer cells is regulated at the mRNA level by a mechanism involving a nontranscriptional activity of p53 and by proteasomal degradation of BIK protein.
- SourceAvailable from: Ching Wooen Sze
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- "As expected, the level of apoptosis induced in the form of caspase-3/7 activation and DNA fragmentation (TUNEL positive cells) was significantly higher in the HCV-infected control cells than in the HCV-infected BIK-depleted cells (Fig. 3B and Fig. S3). Our observation is in accordance with studies from other groups examining the effect of BIK knockdown and apoptosis, where BIKdepleted cells were more resistant to apoptosis induced by various agents (Fu et al., 2007; Hur et al., 2006; Li et al., 2008; Mebratu et al., 2008; Shimazu et al., 2007; Viedma-Rodriguez et al., 2013). In terms of viral induced apoptosis and BIK expression, our observation is in accordance with these studies. "
ABSTRACT: Hepatitis C virus (HCV) induces cytopathic effects in the form of hepatocytes apoptosis thought to be resulted from the interaction between viral proteins and host factors. Using pathway specific PCR array, we identified 9 apoptosis-related genes that are dysregulated during HCV infection, of which the BH3-only pro-apoptotic Bcl-2 family protein, BIK, was consistently up-regulated at the mRNA and protein levels. Depletion of BIK protected host cells from HCV-induced caspase-3/7 activation but not the inhibitory effect of HCV on cell viability. Furthermore, viral RNA replication and release were significantly suppressed in BIK-depleted cells and over-expression of the RNA-dependent RNA polymerase, NS5B, was able to induce BIK expression. Immunofluorescence and co-immunoprecipitation assays showed co-localization and interaction of BIK and NS5B, suggesting that BIK may be interacting with the HCV replication complex through NS5B. These results imply that BIK is essential for HCV replication and that NS5B is able to induce BIK expression.Virology 11/2014; 474. DOI:10.1016/j.virol.2014.10.027 · 3.28 Impact Factor
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- "Suppression of BIK expression by siRNAmediated depletion diminished fulvestrant-induced apoptosis linking BIK to antiestrogeninduced apoptosis. The antiestrogen-induced up-regulation of Bik mRNA was linked to p53 since siRNA-mediated p53 knockdown as well as p53 dominant negative mutant abolished Bik mRNA accumulation (Hur et al., 2006). Surprisingly, this activity of p53 appeared to be unrelated to its DNA-binding activity since fulvestrant treatment did not enhance the DNAbinding activity of p53 in a gelshift assay with oligonucleotide probes containing p53 binding sites. "
ABSTRACT: BIK is the founding member of the BH3-only family pro-apoptotic proteins. BIK is predominantly localized in the ER and induces apoptosis through the mitochondrial pathway by mobilizing calcium from the ER to the mitochondria and remodeling the mitochondrial cristae. BIK-mediated apoptosis is mediated by selective activation of BAX. BIK also induces non-apoptotic cell death in certain cell types by unknown mechanisms. BIK is non-essential for animal development, but appears to be functionally redundant for certain developmental functions with BIM. BIK is implicated in the selection of mature B cells in humans. BIK is a pro-apoptotic tumor suppressor in several human tissues and its expression in cancers is prevented by chromosomal deletions encompassing the Bik locus or by epigenetic silencing. BIK appears to be a critical effector in apoptosis induced by toxins, cytokines and virus infection. Several anti-cancer drugs transcriptionally activate Bik gene expression through transcriptional pathways dependent on factors such as E2F and p53 or by removal of epigenetic marks on the chromatin. BIK appears to be a prominent target for anti-cancer drugs that inhibit proteasomal functions. BIK has also been used as a therapeutic molecule in gene therapy-based approaches to treat difficult cancers.Oncogene 01/2009; 27 Suppl 1(Suppl 1):S20-9. DOI:10.1038/onc.2009.40 · 8.56 Impact Factor
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- "Hence, Bik up-regulation is a common event occurring upon UPS inhibition. Experiments aimed to ablate Bik expression using siRNA have highlighted the contribution of Bik to UPSI induced cell death   . Bik is also important for the sensitization activity of UPSIs towards the death receptor pathway . "
ABSTRACT: Over the past decade, the promising results of UPSIs (UPS inhibitors) in eliciting apoptosis in various cancer cells, and the approval of the first UPSI (Bortezomib/Velcade/PS-341) for the treatment of multiple myeloma have raised interest in assessing the death program activated upon proteasomal blockage. Several reports indicate that UPSIs stimulate apoptosis in malignant cells by operating at multiple levels, possibly by inducing different types of cellular stress. Normally cellular stress signals converge on the core elements of the apoptotic machinery to trigger the cellular demise. In addition to eliciting multiple stresses, UPSIs can directly operate on the core elements of the apoptotic machinery to control their abundance. Alterations in the relative levels of anti and pro-apoptotic factors can render cancer cells more prone to die in response to other anti-cancer treatments. Aim of the present review is to discuss those core elements of the apoptotic machinery that are under the control of the UPS.Current Molecular Pharmacology 01/2008; 1(1):24-37. DOI:10.2174/1874-470210801010024