Study of the subcellular localization of cell cycle regulator Cks1 and its impact on cancer
Progression through the cell cycle is controlled by oscillating waves of cyclins and cyclin-dependent kinases (Cdk). These kinases are regulated positively by association with cyclin regulatory subunits and negatively by binding of Cdk inhibitors. Among the latter, p27 inhibits all cyclin-Cdk complexes regardless of the cell cycle phase and acts as a primary negative regulator of cell proliferation in a variety of cell types and tissues. Intrinsically, phosphorylated p27 is ubiquitinated and degraded by the SCFSkp2-Cks1 complex. Mouse genetic studies and human clinical investigations have shown p27 as an important tumor suppressor, which gene is rarely mutated. However, p27 is frequently downregulated in human cancers due to an increased expression of nuclear Cks1 and this is usually associated with a poor prognosis. The subcellular localization of Cks1 is thus of primordial importance in the control of cell proliferation. Recent results from our laboratory have shown an interaction between Cks1 and nuclear transport proteins α1 and β3 importin. Analysis of the primary sequence of Cks1 also revealed a classic nuclear localization signal (NLS) at its C-terminal. Mutations have been done on the suspected NLS to determine whether or not Cks1’s nuclear import is regulated by this motif. A synthetic inhibitor of β importin has also been used to study the mechanism of Cks1 import. Results indicated that the C-terminal end of Cks1 is indeed a NLS since mutations of Cks1 and inhibition of β importin both lead to accumulation of Cks1 in the cytoplasm. These outcomes were helpful to better understand the mechanism regulating Cks1 localization. However, future works are required to further understand the impact of cytoplasmic sequestration of Cks1 on cancer and hopefully lead to the identification of novel pharmacological targets involved in cell proliferation.
p27 Cks1 Cdk NLS Cyclin Cell cycle Localization Degradation