1. there are three subtypes
RXRa, RXRb, and RXRg (reviewed in (Canan Koch, Dardashti et al. 1996)-5)
2. RXRb info
a) ligands
1) phytanic acid and docosahexaenoic acid, and lithocholic acid compete with 9-cis-RA for binding on RXRb
1. ligand binding to RXRa preferentially promotes the formation of RXR homodimers (Desvergne and Wahli 1999)-114
2. heterodimerization with other nuclear receptors (Schulman, Li et al. 1997)-(Leblanc 1995)
a) permissive with some and nonpermissive with others
1) permissive - PPAR, LXR, and NGFIB
2) nonpermissive – RAR, TR
a) dimerization with these partners causes a decrease in the ability of RXR to bind hormone (Schulman, Li et al. 1997)-(Kurokawa 1994, Forman 1995)
b) also prevents RXR from binding with its ligand (Schulman, Li et al. 1997)-(Kurokawa 1994, Forman 1995)
b) AF-2 domain of RXR is important for the transactivation of partners
1) deletion of the RXR AF-2 domain reduces activation of TR by its hormone (Schulman, Li et al. 1997)-(Leng 1995, Schulman 1996)
2) can recruit corepressors (Schulman, Li et al. 1997)-(Schulman 1996)
c) RXR is the heterodimeric partner for many Class II hormone receptors
3. RXRa is the heterodimerization partner for PPARs (Heyman, Mangelsdorf et al. 1992; Levin, Sturzenbecker et al. 1992)
4. PPAR heterodimerizes with RXR
b) discovery – PPAR acts synergistically with RXR (Kliewer, Umesono et al. 1992) and drives a reporter upstream of a heterologous acyl-CoA oxidase (ACO)PPRE
1) later proven in a natural setting (Issemann, Prince et al. 1993; Keller, Dreyer et al. 1993)
a) PPAR binds with the retinoid X receptor (RXR) (Kliewer, Umesono et al. 1992; Gearing, Gottlicher et al. 1993; Mangelsdorf and Evans 1995)
C1. Expression
1 expression pattern
a) Rev-erba is induced only in the liver, not intestine (Staels, van Tol et al. 1992)
b) RevErba mRNA levels are dramatically increased during differentiation of preadipocytes to adipocytes (Chawla and Lazar 1993)
2. RXRa, b, and g have variable tissue distribution (Clark 2002)-11,12
C2.Differentiation
1. differentiation
a) fat cell differentiation
1) RXRa, though not measureable in pre-adipocytes (undifferentiated 3T3-L1 cells), is induced several fold upon fat cell differentiation (Thuillier, Baillie et al. 1998) (Chawla and Lazar 1993)
b) muscle cell differentiation
1) expression in myoblasts induces muscle differentiation – (Downes, Carozzi et al. 1995)
2. ligands
a) 9-cis retinoic acid binds to RARs (Mangelsdorf, Ong et al. 1990; Heyman, Mangelsdorf et al. 1992; Levin, Sturzenbecker et al. 1992)
2. negative regulation of other nuclear receptors
a) Rev-erba competes with TR for binding to TREs (Downes, Carozzi et al. 1995)
1) Rev-erba binds to TREs consisting of DR-4 sequences (Spanjaard, Nguyen et al. 1994)
C3. Apoptosis
1. anti-apoptosis
a) prevents H2O2 induced apoptosis
1) treatment with all-trans retinoic acid prevented prevented H2O2 induced apoptosis (Konta, Xu et al. 2001)
a) inhibited by treatment with HX531 (2.5mM), an antagonist of RXRa (Konta, Xu et al. 2001)
C4. Retinoids Role
1. retinoids and their role
a) inhibit the growth of cancer cells (Stio, Celli et al. 2001)-5
b) with vitamin D analogues, induce additive growth inhibition of myeloma cells, breast cancer cells (Stio, Celli et al. 2001)-6, and LNCaP prostate cells (Stio, Celli et al. 2001)-7
c) causes hypercalcemia, hypercalciuria, and soft tissue calcification
1) work to develop analogues that have changes in the side chain that lower the calcemic activity
a) may be more effective that 1,25(OH)2D3 at modulating the proliferation and differentiation of various malignant and non-malignant cells (Stio, Celli et al. 2001)-8-13
b) EB 1089 and KH 1060 both have potent anticancer or immunosuppressive properties (Stio, Celli et al. 2001)-14,15
1. AP-1
a) AP-1 is induced in cells treated with H2O2, and this induction is repressed by treatment with all-trans-RA
b) cotreatment with HX531, an RXR-specific inhibitor, prevents the effect on fos but not jun (Konta, Xu et al. 2001)
2. myc
a treatment of SH-SY5Y human neuroblastoma cells with 0.1 and 1 mM 9-cis RA decreases the level of c-myc protein dramatically (Stio, 2001, 213-222)
1 cotreatment with vitamin D analogues synergistically inhibit myc protein levels (Stio, 2001, 213-222)
3. RXRa induces expression of RAR in response to RA treatment
a) anisomycin, or a constitutive active mutant of MKK4 (SEK1) stops the RA induced induction of RARb (Kyriakis 2000)-16
b) MKK4 directly phosphorylated RBRa in a COOH-terminal region (Kyriakis 2000)-16
4. apoC-3
a) RXRa ligands activate this gene (Vu-Dac, Gervois et al. 1998)
5. CRBPII
a) contains an RXRRE and transcription is enhanced by binding of an RXRa homodimers (Tanaka, Hora et al. 2003)-28
b) expression is enhanced by treatment of mice with clofibrate, presumably because PPARa stabilizes RXRa protein expression in vivo (Tanaka, Hora et al. 2003)