CDC25 family dual-specific protein phosphatases activate cyclin-dependent kinases (CDKs) by dephosphorylation of the ATP binding domains of the kinases, functioning as rate-limiting regulators of eukaryotic cell cycle progression. In response to DNA damages, CDC25 phosphatases are inactivated by CHK1/2-dependent phosphorylation, forming critical targets of cell cycle checkpoint. Of mammalian three CDC25 proteins, CDC25A appears to play a distinct and indispensable role in developmental and checkpoint control of the cell cycle, while the functions of CDC25B and CDC25C in development and checkpoint appear more overlapping or dispensable. CDC25A is overexpressed in a variety of human cancer tissues, including breast cancer, although cancer-associated amplification of the CDC25A locus is not usually observed. The long-term goal of this continued research program is to understand the exact role of CDC25A in breast cancer and establish a scientific basis for anti-cancer therapies targeted on this protein. Previous studies indicate that CDC25A overexpression, which is observed in a population of early stage breast cancers, correlates with negative expression of estrogen and progesterone receptors, p53 mutations, high tumor grades and poor prognosis of patients. The central hypothesis evaluated in the present application is that p53 inactivation and deregulated CDC25A expression promote each other with a positive feedback mechanism, and both events functionally cooperate in establishing chromosome instability during tumor initiation and exacerbating malignant phenotypes, especially in triple-negative breast cancer. In the renewed research program, three specific aims will be pursued: (1) Determine how deregulated CDC25A expression cooperates with p53 inactivation in the development of breast cancer;(2) Determine the mechanisms and significance of chromosome instability in mammary epithelial cells with deregulated CDC25A expression;(3) Define in vivo interactions of CDC25A with p53-dependent checkpoint and apoptosis during mammary tumorigenesis. These studies should provide significant insight into the oncogenic roles of CDC25A, which is now regarded as a therapeutic target.
This research program deals with two molecular alterations critical for the development of aggressive forms of breast cancer, CDC25A overexpression and p53 inactivation. Clinical studies indicate a close correlation between the two alterations, while its biological significance is unclear. The proposed studies should provide critical insights and a solid scientific foundation to targeted therapies.
|Bhuripanyo, Karan; Wang, Yiyang; Liu, Xianpeng et al. (2018) Identifying the substrate proteins of U-box E3s E4B and CHIP by orthogonal ubiquitin transfer. Sci Adv 4:e1701393|
|Liu, Xianpeng; Sun, Limin; Gursel, Demirkan B et al. (2017) The non-canonical ubiquitin activating enzyme UBA6 suppresses epithelial-mesenchymal transition of mammary epithelial cells. Oncotarget 8:87480-87493|
|Liu, Xianpeng; Zhao, Bo; Sun, Limin et al. (2017) Orthogonal ubiquitin transfer identifies ubiquitination substrates under differential control by the two ubiquitin activating enzymes. Nat Commun 8:14286|
|Gillam, M P; Nimbalkar, D; Sun, L et al. (2015) MEN1 tumorigenesis in the pituitary and pancreatic islet requires Cdk4 but not Cdk2. Oncogene 34:932-8|
|Zhao, Bo; Villhauer, Eric B; Bhuripanyo, Karan et al. (2014) SUMO-mimicking peptides inhibiting protein SUMOylation. Chembiochem 15:2662-6|
|Liu, Xianpeng; Gu, Xin; Sun, Limin et al. (2014) Downregulation of Smurf2, a tumor-suppressive ubiquitin ligase, in triple-negative breast cancers: involvement of the RB-microRNA axis. BMC Cancer 14:57|
|Bai, Feng; Chan, Ho Lam; Smith, Matthew D et al. (2014) p19Ink4d is a tumor suppressor and controls pituitary anterior lobe cell proliferation. Mol Cell Biol 34:2121-34|
|Zhao, Bo; Zhang, Keya; Bhuripanyo, Karan et al. (2013) Profiling the cross reactivity of ubiquitin with the Nedd8 activating enzyme by phage display. PLoS One 8:e70312|
|Zhao, Bo; Zhang, Keya; Villhauer, Eric B et al. (2013) Phage display to identify Nedd8-mimicking peptides as inhibitors of the Nedd8 transfer cascade. Chembiochem 14:1323-30|
|Masyuk, Tatyana V; Radtke, Brynn N; Stroope, Angela J et al. (2012) Inhibition of Cdc25A suppresses hepato-renal cystogenesis in rodent models of polycystic kidney and liver disease. Gastroenterology 142:622-633.e4|
Showing the most recent 10 out of 20 publications