Transcriptional coregulators: emerging roles of SRC family of coactivators in disease pathology

Abstract

Transcriptional coactivators have evolved as an important new class of functional proteins that participate with virtually all transcription factors and nuclear receptors (NRs) to intricately regulate gene expression in response to a wide variety of environmental cues. Recent findings have highlighted that coactivators are important for almost all biological functions, and consequently, genetic defects can lead to severe pathologies. Drug discovery efforts targeting coactivators may prove valuable for treatment of a variety of diseases.

Coactivator SRC-2–dependent metabolic reprogramming mediates prostate cancer survival and metastasis

“…Tumor cell survival and proliferation are the major hallmarks of the metastatic dissemination of cancer cells to distant sites (42). Given the importance of SRC-2 as the prime coordinator of energy metabolism, which balances growth and survival (43), and its increased expression in metastatic prostate cancer patients (18), we investigated the role of SRC-2 in promoting prostate cancer metastasis. Anchorage-independent growth of tumor cells is a crucial step in the acquisition of malignancy, and silencing of SRC-2 significantly reduced the clonal growth of both C4-2 and PC-3 cells in soft agar (Figure 8, A and B, and Supplemental Figure 11, A and B).…”

The Krüppel-like factors in female reproductive system pathologies

“…The steroid hormones estrogen (E) and progesterone (P), working through their cognate nuclear receptors [estrogen receptor (ESR) 1 and ESR2; progesterone receptor (PGR) -A and PGR-B isoforms] are major regulators of uterine development and function (Hamilton et al ., 2014, Kim et al ., 2013). Their multi-faceted transcriptional pathways involve interactions with numerous nuclear co-regulators (Sangupta & O’Malley, 2014) and result in altered levels of signaling molecules that act through paracrine and autocrine circuits. The underlying mechanism(s) for the autonomous and collective behavior of the multiple cell types of the uterus to maintain function, however, continues to be a work-in-progress, given recent discoveries of new participants and targets.…”

Differential Activation of a Mouse Estrogen Receptor β Isoform (mER β 2) with Endocrine-Disrupting Chemicals (EDCs)

“…Many co-regulators have been implicated in the physiology of reproduction, energy metabolism, inherited human genetic diseases, and cancer (Lonard and O’Malley 2012). SRC-1 was the first member of the p160 family of co-activators to be cloned, after which two additional family members, SRC-2 and SRC-3, were identified (Dasgupta and O’Malley 2014). Our previous studies demonstrated that both SRC2 and p300 co-activate ERα/ERE-mediated activity with BPA, BPAF, and Zea (Li et al 2012).…”