The transcription factor CREB has been extensively studied
The transcription factor CREB has been extensively studied for its role in hippocampus-dependent learning and memory (West et al., 2002, Lonze and Ginty, 2002). Previous research has demonstrated that the phosphorylation of CREB at Ser133, performed by the ERK1/2 signaling pathway, initiates a cascade of transcriptional changes required for LTP in the hippocampus (Wu et al., 2001). As expected, we observed a decrease in the mRNA and protein levels of CREB following ATR treatment, along with a decrease in the protein level of p-CREB in the high-dose ATR-treated group.
We also observed changes to other factors involved in the CREB pathway in our ATR treatment paradigm. BDNF belongs to the family of neurotrophins, and is understood to be a critical factor in neuronal survival, differentiation, synapse formation and LTP regulation, in the hippocampus as well as other crf1 regions (Park and Poo, 2013). The IEG Zif268 is associated with the regulation of the persistence of protein synthesis in hippocampal LTP (Bozon et al., 2003). Both BDNF and Zif268 production are dependent on ERK1/2-mediated phosphorylation of CREB (Bozon et al., 2003, Jeon et al., 2011). In this study, we found that the mRNA and protein levels of BDNF were both reduced following ATR treatment. Interestingly, we observed that the level of Zif268 protein was decreased following ATR treatment, yet there was no significant difference in the mRNA expression level of Zif268 amongst all groups. The quantitative relationship between the level of mRNA and its encoded protein is complex, and can be influenced, amongst other things, by the rate of translation and protein degradation (de Sousa Abreu et al., 2009). Our results therefore indicated that ATR may interfere in the process of translation and/or protein degradation in the hippocampus of rats, which led to the differential expression levels of Zif268 mRNA and protein.
Acknowledgments This work was supported by the National Natural Science Foundation of China (grant number: 81273109).
Introduction Renal cell carcinoma (RCC) is the second leading urogenital malignancy in China, accounting for 2%–3% of all adult cancers. Although an increasing number of patients are detected early with the development of advanced diagnostic technology, approximately 30% of the patients are diagnosed with metastatic RCC (mRCC) or subsequently developed tumor recurrence after surgery. Since mRCC is typically unresponsive to chemotherapy and radiotherapy, immunotherapy consisting of interleukin-2 (IL-2) and interferon-alpha (IFN-α) served as an adjuvant treatment in the 1990s and 2000s, despite low response rates (5%–20%). In recent years, the advent of targeted therapies that inhibit the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways led to a considerable improvement in progression-free survival (PFS) and overall survival (OS) of mRCC patients. However, monotherapy rarely brings in durable disease control, as the benefits of these agents may be undermined by their toxicity and suboptimal tolerability as well as resistance to these agents. Furthermore, because carcinogenesis and the progression of cancer are a biologically complex system, the inhibition of a single target might not lead to thorough disease control. Based on the results from a phase 3 clinical trial, everolimus was only marginally effective in improving the PFS as compared to the placebo (median, 4.9 versus 1.9 months). Multiple clinical trials investigating the efficacy and safety of everolimus and the currently registered drugs (i.e., imatinib, sorafenib, sunitinib, dovitinib, and bevacizumab) for renal cancer combination treatment have shown several adverse effects and limited efficacy. Until 2016, the first successful combination therapy of everolimus and lenvatinib in patients with advanced or metastatic RCC was approved by the FDA,5, 6 thereby rendering cast as the potential treatment for mRCC.