Calcyclin-binding protein or Siah-1-interacting protein (CacyBP/SIP) was previously reported to promote the proliferation of glioma cells. However, the effect of CacyBP/SIP on apoptosis of glioma is poorly understood. Here, our study shows that CacyBP/SIP plays a role in inhibiting doxorubicin (DOX) induced apoptosis of glioma cells U251 and U87. Overexpression of CacyBP/SIP obviously suppressed the DOX-induced cell apoptosis. On the contrary, silencing of CacyBP/SIP significantly promoted it. Further investigation indicated that inhibition of apoptosis by CacyBP/SIP was relevant to its nuclear translocation in response to the DOX treatment. Importantly, we found that the level of p-ERK1/2 in nuclei was related to the nuclear accumulation of CacyBP/SIP. Finally, the role of CacyBP/SIP was confirmed in vivo in a mouse model with the cell line stably silencing CacyBP/SIP. Taken together, our results suggest that CacyBP/SIP plays an important role in inhibiting apoptosis of glioma cells which might be mediated by ERK1/2 signaling pathway, which will provide some guidance for the treatment of glioma. V C 2016 IUBMB Life, 68(3): [211][212][213][214][215][216][217][218][219] 2016
Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) is the most widespread type of liver cancer. However, the underlying mechanism of HCC tumorigenesis is very intricate and HBV-encoded X protein (HBx) has been reported to play a key role in this process. It has been reported that HBx up-regulates the transcription of ErbB3. However, it remains unclear whether HBx can regulate ErbB3 expression at post-translational modification level. In this study, we showed that HBx interacts with ubiquitin ligase Nrdp1 (neuregulin receptor degradation protein 1) and decreases its stability, which results in the up-regulation of ErbB3 and promotion of HCC cells. Moreover, the expression of ErbB3 was almost undetectable in normal liver tissues but was relative abundant in HCC tissues, and the level of ErbB3 and Nrdp1 significantly showed a negative correlation in HCC tissues. Taken together, these findings suggest that HBx promotes the progression of HCC by decreasing the stability of Nrdp1, which results in up-regulation of ErbB3, suggesting that ErbB3 may be a target for HCC therapy.
Our previous studies have illustrated that CacyBP/SIP (Calcyclin-binding protein or Siah-1-interacting protein) promoted the proliferation of glioma cells. However, the possible mechanism still needs to be clarified. In the current study, we aimed to uncover the potential mechanism of CacyBP/SIP in regulating glioma cell proliferation. We found that CacyBP/SIP decreased the protein level of p53, but not the mRNA level of p53 in p53 mutant U251 cell line, whereas, in p53 wild-type U87 cell line, CacyBP/SIP neither promoted its proliferation nor regulated the changes of p53 p rotein. Further investigation indicated that CacyBP/SIP interacted with p53 and Mdm2 (Mouse double minute 2) to promote p53 ubiquitination and subsequent proteasome-mediated degradation in U251. Moreover, in the presence of Mdm2, CacyBP/SIP boosted the ubiquitination of p53 in a dose-dependent manner. On the contrary, inhibition of Mdm2 activity significantly increased the stability of p53. Finally, we found that the protein level of CacyBP/SIP and p53 is inversely correlated in p53 mutant human glioma tissues. These observations suggest an underlying mechanism that CacyBP/SIP promotes the degradation of p53 by enhancing Mdm2 E3 ligase activity, which reveals a novel pathway for the regulation of mutant p53 and provides a new therapeutic approach to target t he CacyBP/SIP-induced glioma cell proliferation. Key words: CacyBP/SIP; p53; Mdm2; glioma; tumorigenesis Glioma is the most common type of brain tumor with the median survival time of only 12 to 15 months, despite the significant improvements in neurosurgery, radiotherapy and chemotherapy [1, 2]. The poor prognosis of glioma is largely attributed to the rapid growth and invasive/migratory nature of glioma cells. Therefore, an understanding of the mechanisms underlying glioma development and progression is critical to discover specific molecular targets that could be served as effective methods for glioma treatment.
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