Cdc25B as a Steroid Receptor Coactivator

Abstract

The traditional role of the Cdc25 family of dual-specificity phosphatases is to activate cyclin-dependent kinases (CDKs) to enable progression through the cell cycle. This chapter reports that in addition to its cell cycle role, Cdc25B functions as a novel steroid receptor coactivator (SRC). When overexpressed in transgenic mammary glands, Cdc25B can up-regulate the expression of two estrogen receptor (ER)-target genes: cyclin D1 and Lactoferrin. In addition, when coexpressed with ER, Cdc25B can coactivate an ER-dependent reporter in the presence of estradiol. The coactivation of Cdc25B can be extended to the glucocorticoid receptor (GR), progesterone receptor (PR), and androgen receptor (AR). Because of the respective importance of ER and AR in breast and prostate cancer, this chapter focuses on the coactivation of both receptors by Cdc25B. We demonstrate that Cdc25B can interact directly with these nuclear receptors, recruit and enhance the activity of histone acetyltransferases (HATs), and potentiate cell-free transcription independent of its cell cycle regulatory function. Furthermore, because Cdc25B is up-regulated in highgrade and poorly differentiated prostate tumors, which are likely transiting from the hormone-dependent to hormone-independent state, we hypothesize that the coactivation of AR by Cdc25B may induce genes responsible for this progression. Taken together, it is highly conceivable that Cdc25B can promote neoplasia by its two disparate functions of (1) coactivation to induce higher levels of expression of steroid receptor target genes and (2) its role of activating CDKs to deregulate progression of the cell cycle, DNA replication, and mitosis. © 2004 Elsevier Inc. All rights reserved.