Cell cycle and hormonal control of nuclear-cytoplasmic localization of theserum- and glucocorticoid-inducible protein kinase, Sgk, in mammary tumor cells - A novel convergence point of anti-proliferative and proliferative cell signaling pathways

The serum- and glucocorticoid-inducible kinase (sgk) is a novel serine/thre onine protein kinase that is transcriptionally regulated in rat mammary tum or cells by serum under proliferative conditions or by glucocorticoids that induce a G(1) cell cycle arrest, Our results establish that the subcellula r distribution of Sgk is under stringent cell cycle and hormonal control. S gk is localized to the perinuclear or cytoplasmic compartment as a 50-kDa h ypophosphorylated protein in cells arrested in G(1) by treatment with the s ynthetic glucocorticoid dexamethasone, In serum-stimulated cells, Sgk was t ransiently hyperphosphorylated and resided in the nucleus. Laser scanning c ytometry, which monitors Sgk localization and DNA content in individual mam mary tumor cells of an asynchronously growing population, revealed that Sgk actively shuttles between the nucleus (in S and G(2)/M) and the cytoplasm (in G(1)) in synchrony with the cell cycle. In cells synchronously released from the G(1)/S boundary, Sgk localized to the nucleus during progression through S phase. The forced retention of exogenous Sgk in either the cytopl asmic compartment, using a wild type sgk gene, or the nucleus, using a nucl ear localization signal-containing sgk gene (NLS-Sgk), suppressed the growt h and DNA synthesis of serum-stimulated cells, Thus, our study implicates t he nuclear-cytoplasmic shuttling of sgk as a requirement for cell cycle pro gression and represents a novel convergence point of anti-proliferative and proliferative signaling in mammary tumor cells.