PERK, one of three key signal transducers localized to the Endoplasmic Reticulum (ER), regulates cell fate in response to proteotoxic stress. PERK activation can be triggered by exposure of cells to physiological stresses such as low energy (glucose deprivation), low oxygen (hypoxia), or by chemical that inhibit protein degradation (bortezomib) or deplete ER calcium stores (thapsigargin). Since tumor survival and progression requires bypass of many of the same stresses that are known to activate PERK, extensive efforts have been undertaken to ascertain whether targeted inhibition of PERK would have therapeutic benefit. Indeed, genetic abrogation of PERK signaling has a profound influence on tumor progression and metastasis supporting the development of small molecule PERK inhibitors. Importantly, the successful use of such small molecules in a clinical setting requires knowledge of both the potential tissue toxicities associated with acute PERK inhibition and a detailed understanding of downstream PERK effectors that contribute to cell growth and survival. To definitively establish the functional role of PERK in the adult tissue, we have generated mice harboring a conditional PERK allele where excision is regulated by tamoxifen administration. In contrast to previous reports, PERK deletion has a profound impact on pancreata regardless of age. This result has profound implications for the utility of small molecule PERK inhibitors and highlights the need to clearly delineate downstream PERK-dependent regulatory pathways. With this in mind, we have set out to define additional pro-survival PERK effector and effector pathways in an effort to develop a more complete understanding of PERK function and ascertain whether any novel effectors might represent opportunities for therapeutic development. The identification and contribution of novel PERK effectors will be discussed.
Citation Format: J. Alan Diehl. Insights into pro-survival signaling by PERK. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY44-02. doi:10.1158/1538-7445.AM2014-SY44-02