Cellular stress triggers TEL nuclear export via two genetically separable pathways

TEL (translocation ets leukemia, also known as ETV6) is a repressor of transcription that is disrupted by the t(12;21), which is the most frequent chromosomal translocation in pediatric acute lymphocytic leukemia. TEL is modified by SUMOylation, and the lysine (Lys 99) that is conjugated to SUMO is required for TEL nuclear export. In addition, TEL is phosphorylated by p38 kinase, which is activated by cellular stress. Induction of cellular stress reduced the ability of TEL to repress transcription in vitro, but the mechanistic basis of this phenomenon was unclear. In this study, we show that osmotic stress causes re‐localization of TEL to the cytoplasm and that p38‐mediated phosphorylation of TEL is sufficient for this re‐localization. However, impairment of both SUMOylation of Lys 99 and p38‐dependent phosphorylation of Ser 257 of TEL were required to impair the re‐localization of TEL in response to cellular stress induced by high salt, identifying two separate nuclear export pathways. Thus, alteration of the cellular localization of TEL may be a part of the cellular stress response and re‐localization of TEL to the cytoplasm is an important step in the regulation of TEL. J. Cell. Biochem. 104: 488–498, 2008. © 2007 Wiley‐Liss, Inc.