Interaction of nuclear receptors with the Wnt/beta-catenin/Tcf signaling axis: Wnt you like to know?
The cross-regulation of Wnt/beta-catenin/Tcf ligands, kinases, and transcription factors with members of the nuclear receptor (NR) family has emerged as a clinically and developmentally important area of endocrine cell biology. Interactions between these signaling pathways result in a diverse array of cellular effects including altered cellular adhesion, tissue morphogenesis, and oncogenesis. Analyses of NR interactions with canonical Wnt signaling reveal two broad themes: Wnt/beta-catenin modulation of NRs (theme I), and ligand-dependent NR inhibition of the Wnt/beta-catenin/Tcf cascade (theme II). Beta-catenin, a promiscuous Wnt signaling member, has been studied intensively in relation to the androgen receptor (AR). Beta-catenin acts as a coactivator of AR transcription and is also involved in co-trafficking, increasing cell proliferation, and prostate pathogenesis. T cell factor, a transcriptional mediator of beta-catenin and AR, engages in a dynamic reciprocity of nuclear beta-catenin, p300/CREB binding protein, and transcriptional initiation factor 2/GC receptor-interaction protein, thereby facilitating hormone-dependent coactivation and transrepression. Beta-catenin responds in an equally dynamic manner with other NRs, including the retinoic acid (RA) receptor (RAR), vitamin D receptor (VDR), glucocorticoid receptor (GR), progesterone receptor, thyroid receptor (TR), estrogen receptor (ER), and peroxisome proliferator-activated receptor (PPAR). The NR ligands, vitamin D(3), trans/cis RA, glucocorticoids, and thiazolidines, induce dramatic changes in the physiology of cells harboring high Wnt/beta-catenin/Tcf activity. Wnt signaling regulates, directly or indirectly, developmental processes such as ductal branching and adipogenesis, two processes dependent on NR function. Beta-catenin has been intensively studied in colorectal cancer; however, it is now evident that beta-catenin may be important in cancers of the breast, prostate, and thyroid. This review will focus on the cross-regulation of AR and Wnt/beta-catenin/Tcf but will also consider the dynamic manner in which RAR/RXR, GR, TR, VDR, ER, and PPAR modulate canonical Wnt signaling. Although many commonalities exist by which NRs interact with the Wnt/beta-catenin signaling pathway, striking cell line and tissue-specific differences require deciphering and application to endocrine pathology.
Mulholland
David J
DJ
Department of Molecular and Medical Pharmacology, 650 Charles E. Young Drive, Center for Health Sciences 23-234, University of California Los Angeles School of Medicine, Los Angeles, CA 90095, USA. dmulholland@mednet.ucla.edu
Dedhar
Shoukat
S
Coetzee
Gerhard A
GA
Nelson
Colleen C
CC
D000818:Animals; D006801:Humans; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051820:TCF Transcription Factors / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D018160:Receptors, Cytoplasmic and Nuclear; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin