Cells have evolved multiple strategies to cope with the varied and inevitable stresses of existence. Perturbation of stress responses underlies numerous diseases. One recently discovered strategy involves the formation of stress granules. We have discovered a novel, unanticipated link between stress granules and the Ser/Thr kinase, RSK2. We found that in breast cancer lines subjected to oxidative stress or serum starvation, endogenous RSK2 associates with and co-localizes with the pro-apoptotic protein, TIA-1, an essential component of stress granules. Unexpectedly, RSK2 regulates stress granule formation through a pathway involving eIF21. Addition of mitogens triggers the dissolution of stress granules, and the released RSK2 accumulates in the nucleus where it induces cyclin D1 expression, driving entry into the cell cycle. We propose a bidirectional regulatory mechanism in which stress granules sequester RSK2 to prevent inappropriate cell cycle entry, and RSK2 facilitates stress granule assembly to repress translation. Thus, RSK2 may be a pivotal factor linking the stress response to survival and proliferation. An essential goal is to elucidate, at a molecular level, the mechanism of this linkage.
The specific aims are: (1) Test the hypothesis that RSK2 controls the stress response through regulation of stress granule assembly. The function of RSK2 in initiation and maintenance of stress granules will be investigated using in vitro binding studies, gene silencing, immunofluorescence and live cell imaging. (2) Test the hypothesis that post-stress recovery depends on RSK2 nuclear translocation. The mechanism of RSK2 nuclear import and the function of RSK2 in survival will be investigated using similar approaches to those used in Aim 1. These studies will increase our mechanistic understanding of the function of RSK2 in promoting disease, in particular cancer, and may identify new targets for therapeutic intervention.
We have discovered a novel mechanism that links the protein kinase RSK2 with survival in response to stress. Perturbation of stress responses underlies numerous diseases. Our studies may identify new targets for therapeutic intervention in cancer and inflammatory diseases.
|Mrozowski, Roman M; Sandusky, Zachary M; Vemula, Rajender et al. (2014) De novo synthesis and biological evaluation of C6â€³-substituted C4â€³-amide analogues of SL0101. Org Lett 16:5996-9|
|Hilinski, Michael K; Mrozowski, Roman M; Clark, David E et al. (2012) Analogs of the RSK inhibitor SL0101: optimization of in vitro biological stability. Bioorg Med Chem Lett 22:3244-7|
|Pasic, Lejla; Eisinger-Mathason, T S Karin; Velayudhan, Bisi T et al. (2011) Sustained activation of the HER1-ERK1/2-RSK signaling pathway controls myoepithelial cell fate in human mammary tissue. Genes Dev 25:1641-53|
|Groehler, Angela L; Lannigan, Deborah A (2010) A chromatin-bound kinase, ERK8, protects genomic integrity by inhibiting HDM2-mediated degradation of the DNA clamp PCNA. J Cell Biol 190:575-86|
|Eisinger-Mathason, T S Karin; Andrade, Josefa; Lannigan, Deborah A (2010) RSK in tumorigenesis: connections to steroid signaling. Steroids 75:191-202|
|Eisinger-Mathason, T S Karin; Andrade, Josefa; Groehler, Angela L et al. (2008) Codependent functions of RSK2 and the apoptosis-promoting factor TIA-1 in stress granule assembly and cell survival. Mol Cell 31:722-36|