Aurora-A Abrogation of p53 DNA Binding and Transactivation Activity by Phosphorylation of Serine 215

Abstract

The tumor suppressor p53 is important in the decision to either arrest cell cycle progression or induce apoptosis in response to a variety of stimuli. Cip/WAF1 and PTEN, were inhibited by Aurora-A in a Ser-215 phosphorylation-dependent manner (i.e. phosphomimic p53-S215D lost and nonphosphorylatable p53-S215A retained normal p53 function). As a result, Aurora-A overrides the apoptosis and cell cycle arrest induced by cisplatin and ␥-irradiation, respectively. However, the effect of Aurora-A on p53 DNA binding and transactivation activity was not affected by phosphorylation of Ser-315, a recently identified Aurora-A phosphorylation site of p53

Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation

“…In contrast, it was shown in cultured cells that overexpression of Aurora-A phosphorylates p53, leading to its degradation Liu et al, 2004). It is therefore proposed that expression of Aurora-A induces tumorigenesis through degradation of p53 Liu et al, 2004). Differing from these studies, we found that overexpression of Aurora-A in mammary epithelium of our MMTV-Aurora-A transgenice mice did not cause an obvious alteration in p53 protein levels, nor an increase in apoptosis.…”

“…Zhang et al (2004) also reported that overexpression of Aurora-A in mammary epithelium induced an accumulation of p53 and p53-dependent apoptosis. In contrast, it was shown in cultured cells that overexpression of Aurora-A phosphorylates p53, leading to its degradation Liu et al, 2004). It is therefore proposed that expression of Aurora-A induces tumorigenesis through degradation of p53 Liu et al, 2004).…”

“…Further studies revealed that the transforming ability of Aurora-A might be correlated with phosphorylation of p53 at serine 215 (S215) and S315. The phosphorylation of these sites is responsible for the inactivation of p53 transactivation activity and degradation of p53, respectively Liu et al, 2004). It was recently shown that Aurora-A physically binds and phosphorylates BRCA1 at S308 (Ouchi et al, 2004).…”

BimEL is phosphorylated at mitosis by Aurora A and targeted for degradation by βTrCP1

“…The p53 tumor suppressor was shown to be phosphorylated by Aurora A leading to destabilization and degradation of the p53 protein in a mechanism reminiscent of what we have observed for BimEL. 47,48 Similarly, Aurora A was shown to phosphorylate BRCA1 and promote G2/M cell cycle progression. 49 Thus, in addition to the wide range of substrates targeted by Aurora A regulating chromosome and spindle dynamics during mitosis, it can also phosphorylate and deactivate tumor-suppressor pathways including Bim.…”

Overexpression of Aurora-A kinase promotes tumor cell proliferation and inhibits apoptosis in esophageal squamous cell carcinoma cell line

“…Aurora, a subfamily of serine/threonine protein kinase, includes Aurora-A, Aurora-B and Aurora-C in vertebrates [5]. Increased attention has now been focused on Aurora-A kinase because of its amplification and overexpression in several types of human tumors, such as breast cancer [6], colorectal cancers [7] and pancreatic cancer [8].…”