Phosphorylation of p53 Is Regulated by TPX2-Aurora A in Xenopus Oocytes

Abstract

p53 is an important tumor suppressor regulating the cell cycle at multiple stages in higher vertebrates. The p53 gene is frequently deleted or mutated in human cancers, resulting in loss of p53 activity. This leads to centrosome amplification, aneuploidy, and tumorigenesis, three phenotypes also observed after overexpression of the oncogenic kinase Aurora A. Accordingly, recent studies have focused on the relationship between these two proteins. p53 and Aurora A have been reported to interact in mammalian cells, but the function of this interaction remains unclear. We recently reported that Xenopus p53 can inhibit Aurora A activity in vitro but only in the absence of TPX2. Here we investigate the interplay between Xenopus Aurora A, TPX2, and p53 and show that newly synthesized TPX2 is required for nearly all Aurora A activation and for full p53 synthesis and phosphorylation in vivo during oocyte maturation. In vitro, phosphorylation mediated by Aurora A targets serines 129 and 190 within the DNA binding domain of p53. Glutathione S-transferase pull-down studies indicate that the interaction occurs via the p53 transactivation domain and the Aurora A catalytic domain around the T-loop. Our studies suggest that targeting of TPX2 might be an effective strategy for specifically inhibiting the phosphorylation of Aurora A substrates, including p53.

TPX2 in human clear cell renal carcinoma: Expression, function and prognostic significance

“…TPX2 is a cell cycle protein and serves a key role in the stability of the mitotic spindle (18). As a microtubule-associated protein, TPX2 tightly adheres to the mitotic spindle in mitotic cells (28). In certain tumors, overexpression of TPX2 results in centrosome amplification and heteroploidy formation (29,30).…”

TPX2 (TPX2, microtubule-associated, homolog (Xenopus laevis))

“…DNA damage response (DDR): recent data show that TPX2 is involved in DDR to ionising radiations, by modulating the levels of γ-H2AX; TPX2 localises to DNA double strand breaks and interacts with DDR factors such as MDC1 (Neumayer et al, 2012). Previous data suggested a link between TPX2 and DDR: i) TPX2 is a putative substrate of the ATM/ATR kinases, as revealed in a large-scale proteomic screening (Matsuoka et al, 2007); ii) a functional interplay has been shown between Xenopus TPX2, the Aurora-A kinase and the p53 oncosuppressor (Pascreau et al, 2009). …”

TPX2 siRNA regulates growth and invasion of esophageal cancer cells

“…It is a microtubule-associated protein that plays an important role for the stability of the mitotic spindle [10]. Human TPX2, as a cell cycle protein [30], can closely combine with mitotic spindle in mitotic cells. TPX2 has been documented to be highly expressed in lung squamous cell carcinoma, salivary gland carcinoma, and ovarian cancer [8,9,31], but there were few reports about TPX2 expression in esophageal squamous cell carcinoma cases.…”