Negatively regulated by controlled degradation through its antagonists including Mdm2, Mdm4 and COP1, the tumor suppressor p53 have a high turn-around rate and low physiological levels. Upon DNA damage stress, p53 is rapidly stabilized and transcriptionally regulates a broad array of genes that mediate cell cycle arrest, cellular senescence, DNA repair, and apoptosis. Accumulating evidence suggests that ATM/ATR-mediated phosphorylation of Mdm2, Mdm4 and COP1 accelerates their degradation, which may be the initial driving force to induce p53 during the early DNA damage response. When the cell returns to its normal state following DNA repair, p53 needs to be simultaneously reduced. Very little is known about how the DNA damage response is `deactivated'following repair. Recent evidence suggests that a novel protein phosphatase, Wip1 (or PPM1D), contributes to closing the activation loop initiated by ATM/ATR kinases to provide p53 a homeostatic regulation. Our preliminary results showed that Wip1 stabilizes Mdm2 by dephosphorylating its ATM targeted Ser395, resulting in decreased levels of p53. We also showed that Wip1 dephosphorylates Mdm4 and COP1 in vitro at their ATM targeting sites. If aberrantly regulated, Wip1 becomes an oncogenic phosphatase that inhibits ATM/ATR DNA damage response and p53 tumor suppressor pathways. The Wip1 gene is amplified in a number of human cancers expressing wildtype p53, suggesting it possesses oncogenic functions in tumor progression. Wip1 knockout mice are resistant to spontaneous tumors, consistent with their up-regulated p53 activity. The hypothesis to be tested is that Wip1 regulates p53 primarily through dephosphorylating its antagonists (Mdm2, Mdm4 and COP1) in the ATM/ATR DNA damage response pathway.
The Wip1 gene encodes an enzyme that removed phosphate from proteins and deactivates them. It is amplified in several human cancers including breast cancer, ovary cancer, pancreatic cancer and prostate cancer. The goal of this research project is to (1) clarify the functions of Wip1 in the ATM (Ataxia Telangiectasia Mutated) initiated DNA damage response pathway;(2) determine if inhibiting Wip1 would rescue ATM deficiency in Ataxia Telangiectasia patients.
|Zhou, Yunfei; Wan, Guohui; Spizzo, Riccardo et al. (2014) miR-203 induces oxaliplatin resistance in colorectal cancer cells by negatively regulating ATM kinase. Mol Oncol 8:83-92|
|Wan, Guohui; Liu, Yunhua; Han, Cecil et al. (2014) Noncoding RNAs in DNA repair and genome integrity. Antioxid Redox Signal 20:655-77|
|Han, Cecil; Liu, Yunhua; Wan, Guohui et al. (2014) The RNA-binding protein DDX1 promotes primary microRNA maturation and inhibits ovarian tumor progression. Cell Rep 8:1447-60|
|Wan, Guohui; Mathur, Rohit; Hu, Xiaoxiao et al. (2013) Long non-coding RNA ANRIL (CDKN2B-AS) is induced by the ATM-E2F1 signaling pathway. Cell Signal 25:1086-95|
|Wan, Guohui; Hu, Xiaoxiao; Liu, Yunhua et al. (2013) A novel non-coding RNA lncRNA-JADE connects DNA damage signalling to histone H4 acetylation. EMBO J 32:2833-47|
|Zhao, Luqing; Lu, Xiongbin; Cao, Ya (2013) MicroRNA and signal transduction pathways in tumor radiation response. Cell Signal 25:1625-34|
|Wan, Guohui; Zhang, Xinna; Langley, Robert R et al. (2013) DNA-damage-induced nuclear export of precursor microRNAs is regulated by the ATM-AKT pathway. Cell Rep 3:2100-12|
|Lu, Zengxin; Wan, Guohui; Guo, Huarong et al. (2013) Protein phosphatase 1 inhibits p53 signaling by dephosphorylating and stabilizing Mdmx. Cell Signal 25:796-804|
|Darlington, Y; Nguyen, T-A; Moon, S-H et al. (2012) Absence of Wip1 partially rescues Atm deficiency phenotypes in mice. Oncogene 31:1155-65|
|Zhang, Xinna; Wan, Guohui; Berger, Franklin G et al. (2011) The ATM kinase induces microRNA biogenesis in the DNA damage response. Mol Cell 41:371-83|
Showing the most recent 10 out of 17 publications