This project aims to understand the non-canonical activity of retinoic acid (RA) signaling. These studies will employ embryonic stem (ES) cell culture as the experimental model system. Oct4 (Pou5f1) is the """"""""master regulator"""""""" of pluriopotent stem cells including ES, and its expression level must be maintained within a narrow range to ensure the """"""""stemness"""""""" feature of ES. A constant level of Oct4 expression depends upon promyelocytic leukemia (Pml) protein and a particular nuclear structure called Pml-nuclear body (Pml-NB). Our preliminary data show RA exerts a non-canonical activity that rapidly activates Extracellular signal Regulated Kinase 1/2 (ERK1/2), regulates specific proteins'post-translational modification (PTM) and disrupts Pml-NB with which the Oct4 basal promoter is physically associated. This Pml-NB structure is also important for inter- chromosomal coordination of the Oct4 locus with another key stem cell locus Nanog located on a different chromosome. Therefore, the non-canonical activity of RA disrupts Pml-NB, lowers Oct4 and Nanog expression levels and affects the """"""""stemness"""""""" property of ES. We propose a principal hypothesis that in ES cells, the non- canonical RA-activated ERK1/2 alters specific proteins'PTM and regulates the Pml-NB structure which is critical to coordinated regulation of multiple key genomic loci such as Oct4 and Nanog, and ultimately affects the stem cell fate. We propose two aims to understand these newly identified effects of RA. Specifically, aim 1 will examine the non-canonical activity of RA transmitted, at least partially, through ERK1/2 activation to post- translationally modify specific proteins.
Aim 2 will examine how this activity rapidly affects the sub-nuclear structure Pml-NB to facilitate an environment coordinating multiple gene regulation/chromatin remodeling of multiple loci such as Oct4/Nanog loci in ES cells, thereby affecting stem cell fate. Completion of these studies will allow us to construct a more comprehensive picture of how RA signal can be transmitted, through canonical and non-canonical pathways, to modulate the overall health of the cells including ES cells. Understanding these new mechanisms of action of RA will facilitate the manipulation of these specific RA signaling pathways to improve the efficacy of its application as a therapeutic agent/nutrient, and to minimize its serious toxic effects. These studies will also shed lights on the maintenance of ES cell culture with respect to its extreme sensitivity to RA/vitamin A in the culture medium. Furthermore, this non-canonical RA activity may be a key to """"""""epigenetic"""""""" changes caused by RA applied as a therapeutic agent in diseased conditions.
Retinoic acid (RA), the biologically active form of Vitamin A, is essential for a variety of biological processes. RA functions by primarily regulating target gene expression, but it also augments other biological process through non-canonical activities. The long-term goal of this project is to understand how vitamin A affects health and diseases. The current proposal focuses on the non-canonical effects of vitamin A, in particular with regards to the maintenance of embryonic stem cells.
|Persaud, Shawna D; Park, Sung Wook; Ishigami-Yuasa, Mari et al. (2016) All trans-retinoic acid analogs promote cancer cell apoptosis through non-genomic Crabp1 mediating ERK1/2 phosphorylation. Sci Rep 6:22396|
|Lin, Yi-Wei; Lee, Bomi; Liu, Pu-Ste et al. (2016) Receptor-Interacting Protein 140 Orchestrates the Dynamics of Macrophage M1/M2 Polarization. J Innate Immun 8:97-107|
|Adhikari, Neeta; Shekar, Kadambari Chandra; Staggs, Rodney et al. (2015) Guidelines for the isolation and characterization of murine vascular smooth muscle cells. A report from the International Society of Cardiovascular Translational Research. J Cardiovasc Transl Res 8:158-63|
|Feng, Xudong; Lin, Yu-Lung; Wei, Li-Na (2015) Behavioral stress reduces RIP140 expression in astrocyte and increases brain lipid accumulation. Brain Behav Immun 46:270-9|
|Lin, Yi-Wei; Liu, Pu-Ste; Adhikari, Neeta et al. (2015) RIP140 contributes to foam cell formation and atherosclerosis by regulating cholesterol homeostasis in macrophages. J Mol Cell Cardiol 79:287-94|
|Wei, Li-Na; Dmintrovsky, Ethan (2015) Retinoids are back. FASEB J 29:1131-5|
|Liu, Pu-Ste; Lin, Yi-Wei; Lee, Bomi et al. (2014) Reducing RIP140 expression in macrophage alters ATM infiltration, facilitates white adipose tissue browning, and prevents high-fat diet-induced insulin resistance. Diabetes 63:4021-31|
|Hall, Jennifer L; Wei, Li-Na (2014) Could silencing IRF5 improve healing of a myocardial infarct through the reprogramming of the macrophage population? J Am Coll Cardiol 63:1567-8|
|Flaisher-Grinberg, S; Tsai, H C; Feng, X et al. (2014) Emotional regulatory function of receptor interacting protein 140 revealed in the ventromedial hypothalamus. Brain Behav Immun 40:226-34|
|Feng, X; Wu, C-Y; Burton, F H et al. (2014) *-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia. Cell Death Differ 21:397-406|
Showing the most recent 10 out of 89 publications