Novel RSK-medicated Survival and Proliferation Processes in Normal and Transformed Mammary Epithelial Cells

Precise regulation of cellular proliferation and survival is essential for normal development and homeostasis. Hyperproliferation can lead to malignancy while premature cell death contributes to many different human pathologies, including diabetes, and neurodegenerative disorders. The Serine/Threonine kinases ribosomal S6 kinase 1 (RSK1) and ribosomal S6 kinase 2 (RSK2) regulate multiple aspects of survival and proliferation. Here we report the discovery of two novel RSK-mediated processes that control cellular stress responses and metabolism, essential components of cell survival and proliferation. First we report a new role for RSK2 in the cellular stress response. RSK2 is a key component of stress granules (SGs) in MCF-7 breast cancer cells subjected to oxidative stress. SGs are RNA granules that form in the cytoplasm of cells exposed to various types of stress. Specific mRNAs are stored in the granules and are protected from degradation. We have found that RSK2 interacts directly with the essential SG marker, (T cell intracellular antigen-1) TIA-1. Importantly, decreased RSK2 levels significantly reduced the ability of breast cell lines to survive oxidative stress. Consistent with these data, knockdown of RSK2, by short hairpin RNA, in primary human epithelial cells followed by treatment with the oxidative stressor, sodium arsenite, caused an increase in cleaved caspase 3 levels. Together, these data indicate that RSK2 functions in cell survival by facilitating SG function. Mitogen releases RSK2 from the SGs and permits nuclear import. Nuclear accumulation of RSK2 is dependent on TIA-1. Surprisingly, nuclear localization of   RSK2 is sufficient to enhance proliferation through induction of cyclin D1, in the  absence of other active signaling pathways. Hence, RSK2 is a pivotal factor linking the stress response to survival and proliferation. Second, we have found an unanticipated link between cellular metabolism and RSK1 in breast cancer cells. In transformed breast cells endogenous RSK1 accumulates in the mitochondria where it regulates mitochondrial membrane potential. Silencing RSK1 depolarizes mitochondria and reduces ATP production, suggesting that RSK1 is an important regulator of metabolism. RSK1 knockdown also decreases intracellular glucose levels, potentially linking glucose regulation and mitochondrial activity. RSK1 regulates mitochondrial membrane potential in breast cancer cells, but not normal cells. Interestingly, mitochondria of normal cells lack accumulated RSK1. Hence, RSK1 accumulates in mitochondria and specifically promotes multiple aspects of metabolism in transformed cells.

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