Xia Zhang

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• Zhang, D. D., Chen, W., Wang, H., Tao, S., Zhang, D. D., Wu, W., Lian, F., Jaramillo, M., Fang, D., & Zhang, D. D. (2013). Tumor protein translationally controlled 1 is a p53 target gene that promotes cell survival. Cell cycle (Georgetown, Tex.), 12(14).
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  Tumor suppressor p53 maintains genome stability by differentially activating target genes that control diverse cellular responses, such as the antioxidant response, cell cycle arrest and apoptosis. Despite the fact that many p53 downstream genes have been well characterized, novel p53 target genes are continuously being identified. Here, we report that Tpt1 is a direct target gene of p53. We found that p53 upregulates the transcription of Tpt1 and identified a p53-responsive element in the promoter of the mouse Tpt1 gene. Furthermore, p53-dependent induction of Tpt1 was able to reduce oxidative stress, minimize apoptosis, and promote cell survival in response to H 2O2 challenge. In addition, a positive correlation between the expression of p53 and Tpt1 only existed in normal lung tissues, not in lung tumors. Such positive correlation was also found in lung cell lines that contain wild-type p53, but not mutated p53. Based on the important role of Tpt1 in cancer development, chemoresistance, and cancer reversion, identification of Tpt1 as a direct target gene of p53 not only adds to the complexity of the p53 network, but may also open up a new avenue for cancer prevention and intervention.
• Zhang, D. D., Goff, S. A., & Zhang, D. D. (2013). Heterosis in elite hybrid rice: speculation on the genetic and biochemical mechanisms. Current opinion in plant biology, 16(2).
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  Because of the tremendous advances in functional genomics and the current availability of a large number of superior hybrids, rice is an excellent model crop system for heterosis research. Genetic dissection of yield and yield component traits of an elite rice hybrid using an ultra-high density linkage map identified overdominance as the principal genetic basis of heterosis in this hybrid. This is not an expected finding based on the reported effects of single genes. Here we propose a gene expression and protein quality control hypothesis as one possible explanation for the overdominance in hybrids bred for yield. Future studies will be directed toward the identification of the genetic and biochemical mechanisms underlying the biology of hybrid vigor.
• Zhang, D. D., Lau, A., Zhang, D. D., Tao, S., Wang, H., Whitman, S. A., White, E., & Zhang, D. D. (2013). Arsenic inhibits autophagic flux, activating the Nrf2-Keap1 pathway in a p62-dependent manner. Molecular and cellular biology, 33(12).
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  The Nrf2-Keap1 signaling pathway is a protective mechanism promoting cell survival. Activation of the Nrf2 pathway by natural compounds has been proven to be an effective strategy for chemoprevention. Interestingly, a cancer-promoting function of Nrf2 has recently been observed in many types of tumors due to deregulation of the Nrf2-Keap1 axis, which leads to constitutive activation of Nrf2. Here, we report a novel mechanism of Nrf2 activation by arsenic that is distinct from that of chemopreventive compounds. Arsenic deregulates the autophagic pathway through blockage of autophagic flux, resulting in accumulation of autophagosomes and sequestration of p62, Keap1, and LC3. Thus, arsenic activates Nrf2 through a noncanonical mechanism (p62 dependent), leading to a chronic, sustained activation of Nrf2. In contrast, activation of Nrf2 by sulforaphane (SF) and tert-butylhydroquinone (tBHQ) depends upon Keap1-C151 and not p62 (the canonical mechanism). More importantly, SF and tBHQ do not have any effect on autophagy. In fact, SF and tBHQ alleviate arsenic-mediated deregulation of autophagy. Collectively, these findings provide evidence that arsenic causes prolonged activation of Nrf2 through autophagy dysfunction, possibly providing a scenario similar to that of constitutive activation of Nrf2 found in certain human cancers. This may represent a previously unrecognized mechanism underlying arsenic toxicity and carcinogenicity in humans.
• Zhang, D. D., Tao, S., Zhang, D. D., Lau, A., Jaramillo, M. C., Chau, B. T., Lantz, R. C., Wong, P. K., Wondrak, G. T., & Zhang, D. D. (2013). Tanshinone I Activates the Nrf2-Dependent Antioxidant Response and Protects Against As(III)-Induced Lung Inflammation In Vitro and In Vivo. Antioxidants & redox signaling.
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  Abstract Aims: The NF-E2 p45-related factor 2 (Nrf2) signaling pathway regulates the cellular antioxidant response and activation of Nrf2 has recently been shown to limit tissue damage from exposure to environmental toxicants, including As(III). In an attempt to identify improved molecular agents for systemic protection against environmental insults, we have focused on the identification of novel medicinal plant-derived Nrf2 activators. Results: Tanshinones [tanshinone I (T-I), tanshinone IIA, dihydrotanshinone, cryptotanshinone], phenanthrenequinone-based redox therapeutics derived from the medicinal herb Salvia miltiorrhiza, have been tested as experimental therapeutics for Nrf2-dependent cytoprotection. Using a dual luciferase reporter assay overexpressing wild-type or mutant Kelch-like ECH-associated protein-1 (Keap1), we demonstrate that T-I is a potent Keap1-C151-dependent Nrf2 activator that stabilizes Nrf2 by hindering its ubiquitination. In human bronchial epithelial cells exposed to As(III), T-I displays pronounced cytoprotective activity with upregulation of Nrf2-orchestrated gene expression. In Nrf2 wild-type mice, systemic administration of T-I attenuates As(III) induced inflammatory lung damage, a protective effect not observed in Nrf2 knockout mice. Innovation: Tanshinones have been identified as a novel class of Nrf2-inducers for antioxidant tissue protection in an in vivo As(III) inhalation model, that is relevant to low doses of environmental exposure. Conclusion: T-I represents a prototype Nrf2-activator that displays cytoprotective activity upon systemic administration targeting lung damage originating from environmental insults. T-I based Nrf2-directed systemic intervention may provide therapeutic benefit in protecting other organs against environmental insults. Antioxid. Redox Signal. 00, 000-000.