Loss of p14(ARF) confers resistance to heat shock- and oxidative stress-mediated cell death by upregulating ß-catenin.

ABSTRACT

The p14(ARF) is a key tumor suppressor induced mainly by oncogenic stimuli. Although p14(ARF) does not seem to respond to DNA damage, there are very few data regarding its role in other forms of stress, such as heat shock (HS) and oxidative stress (OS). Here, we report that suppression of p14(ARF) increased resistance to cell death when cells were treated with H(2) O(2) or subjected to HS. In this setting, protection from cell death was mediated by elevated levels and activity of ß-catenin, as downregulation of ß-catenin alleviated the protective role of p14(ARF) silencing. Moreover, Hsp70 was shown to regulate ß-catenin protein levels by interacting with p14(ARF) , suggesting that Hsp70, p14(ARF) and ß-catenin form a regulatory network. This novel pathway triggers cell death signals when cells are exposed to HS and OS.