Cyclins, cyclin dependent kinases, and regulation of steroid receptor action

Abstract

Steroid receptors (SR), which are ligand activated transcription factors, and their coactivators are phosphoproteins whose activities are regulated by cell signaling pathways. Many of the identified phosphorylation sites in these proteins contain Ser/Thr-Pro motifs suggesting that they are substrates for cyclin dependent kinases and/or for mitogen activated protein kinases. An analysis of the roles of cyclins and their kinases in regulating receptor action has revealed that there are both stimulatory and inhibitory actions of cyclins, that some of the actions are independent of the partner kinases and that these activities are receptor specific. Consistent with this finding, the limited analyses of receptor activity as a function of cell cycle reveal distinct patterns of activation. SR often regulate cell proliferation. Thus, the cross-talk between cyclins and their kinases and the SR provides a means for integrating the actions of the SR with the cell cycle status of cells.

Figure 1

Model for steroid receptor (SR) action. Steroid hormones difuse across the cell membrane where they bind to their cognate receptor in the cytoplasm of target cells. Ligand binding induces conformational changes in the receptor, dissociation of heat shock proteins (HSPs), dimerization and nuclear translocation. In the classical mechanism for SR action, the SR dimer binds to specific DNA response elements situated in the regulatory regions of target genes. This is followed by recruitment of coactivators, such as p160s, cyclins, p300/CBP and pCAF, and other components of the general transcription machinery enabling RNA synthesis. SRs also influence transcription regulated by other transcription factors (TFs) through protein-protein interactions and coactivator recruitment rather than DNA binding. These mechanisms are in turn influenced by phosphorylation of the receptor by multiple kinase pathways such as Src, MAPK, Ras, Raf and G-proteins. Both cytoplasmic and membrane bound receptors (mSRs) influence kinase signaling cascades leading to the phosphorylation of transcription factors. Other steroid responsive receptors with no homology to nuclear receptors are also capable of altering cellular signaling.