Disease relevance of RIEG2

• Thus, proteasomal regulation of RGS expression in HEK293 cells strongly controls RGS function and a novel RGS2 mutation with decreased protein expression could be relevant to the pathophysiology of hypertension in humans [1].
• These effects were blocked in cells infected with the adenovirus expressing RGS2 [2].
• These results indicate that RGS2 is an important negative-regulatory factor in cardiac hypertrophy produced by alpha(1)-adrenergic receptor stimulation through complex mechanisms involving the modulation of mitogen-activated protein kinase signaling pathways [2].
• Axenfeld-Rieger Syndrome (ARS) is a genetically heterogeneous birth defect characterized by malformation of the anterior segment of the eye associated with glaucoma [3].
• The ocular component of the ARS phenotype has acquired most clinical attention and has been dissected into a spectrum of developmental eye disorders, of which open-angle glaucoma represents the main challenge in terms of treatment [4].

Psychiatry related information on RIEG2

• The Symptom Checklist-90-R, Hamilton Anxiety (HAM-A), and Akathisia Rating (ARS) scales were administered [5].
• Co-regulation of brain ACHE and ARS was suggested from their mutually increased expression following acute psychological stress [6].
• Parents and teachers of the children completed the DuPaul's attention deficit hyperactivity disorder (ADHD) rating scale (ARS; Korean version, K-ARS) and Child Behavior Checklists [7].

High impact information on RIEG2

• Genome data reveal a growing number of open reading frames encoding ARS-like proteins [8].
• In wild-type cells treated with HU, early ARS elements replicated but late ones did not [9].
• Mutations in PITX2 associated with Axenfeld-Rieger syndrome (ARS) provided the first link of this homeodomain transcription factor to tooth development [10].
• Altogether these data suggest a molecular mechanism for tooth development involving Dlx2 gene expression in ARS patients [10].
• For the first time, we present evidence that increased PITX2 activity may underlie the severe ARS ocular phenotype [11].

Chemical compound and disease context of RIEG2

• We next investigated the effects of RGS2 overexpression produced by infecting cells with an adenovirus encoding RGS2-cDNA on cardiomyocyte responses to PE [2].
• Here, we identified RGS2 as a gene specifically downregulated in androgen-independent prostate cancer cells [12].
• In this study, we show that HMN-176 circumvents multidrug resistance in a K2 human ovarian cancer subline selected for Adriamycin resistance (K2/ARS) [13].
• ARS Presidential Address: Estrogen therapy: a causal role in endometrial cancer [14]?
• The synergists piperonyl butoxide and S,S,S-tributylphosphorotrithioate increased t-permethrin toxicity four- and threefold (at the LC50) in the UF and ARS colonies, respectively [15].

Biological context of RIEG2

• Direct sequencing of FKHL7 detected a C67T mutation that segregated with the ARS phenotype in this family, but was not detected in over 80 control chromosomes [16].
• Missense mutations of the PITX2 homeodomain identified in IH (Arg46Trp), IGDS (Arg31His) and ARS patients (Leu16Gln; Thr30Pro; Arg53Pro) were introduced into recombinant PITX2 cDNA by site-directed mutagenesis [17].
• The PITX2 T68P ARS mutation occurs at a protein kinase C phosphorylation site in the homeodomain [10].
• ARS patients present with iris hypoplasia, a prominent Schwalbe line, adhesions between the iris stroma and the iridocorneal angle and increased intraocular pressure [18].
• Furthermore, cell surface biotinylation indicated that the inhibitory effect of RGS2 on TRPV6 activity is not mediated by differences in trafficking or retrieval of TRPV6 from the plasma membrane [19].

Anatomical context of RIEG2

• PITX2 mutant proteins expressed in COS-7 cells were determined to be stable and localized to the nucleus; however, the Arg53Pro ARS mutant also displayed cytoplasmic staining [17].
• To assess the role of endogenous RGS2, we characterized G(s) and G(q) signaling in osteoblasts derived from wild type and rgs2(-/-) mice [20].
• We report that both H295R cells and human adrenal gland express RGS2 mRNA [21].
• RGS2 promotes formation of neurites by stimulating microtubule polymerization [22].
• Immunocytochemical analysis showed that endogenous RGS2 was localized at the termini of neurites in differentiated PC12 cells [22].

Associations of RIEG2 with chemical compounds

• In contrast, a destabilizing mutation in RGS2 (RGS2-Q2L) recently identified as a rare N-terminal genetic variant in a Japanese hypertensive cohort (J Hypertens 23:1497-1505, 2005) showed significantly reduced expression and inhibition of angiotensin II (AT(1)) receptor-stimulated accumulation of inositol phosphates [1].
• N-Terminal Residues Control Proteasomal Degradation of RGS2, RGS4, and RGS5 in Human Embryonic Kidney 293 Cells [1].
• By yeast two-hybrid and glutathione S-transferase pulldown analysis we identified RGS2 as a novel TRPV6-associated protein [19].
• RGS2 overexpression by retroviral infection in H295R cells caused a decrease in Ang II-stimulated aldosterone secretion but did not modify cortisol secretion [21].
• RGS2 is regulated by angiotensin II and functions as a negative feedback of aldosterone production in H295R human adrenocortical cells [21].

Regulatory relationships of RIEG2

• PITX2 DeltaT1261 is unable to interact with a cellular factor to synergistically activate transcription and demonstrates the first link of ARS with defective PITX2 protein interactions [23].

Other interactions of RIEG2

• Haplotypic analysis of three Rieger syndrome regions in a large family with Axenfeld-Rieger syndrome excluded linkage to the 4q25 (PITX2), 6p25 (FOXC1), and 13q14 (RIEG2) regions [24].
• We report on a three-generation family with Axenfeld-Rieger syndrome (ARS), harboring an alteration in the FKHL7 gene [16].

Analytical, diagnostic and therapeutic context of RIEG2

• In H295R cells, Ang II caused a rapid and transient increase in RGS2 mRNA levels quantified by real-time RT-PCR [21].
• Western blotting showed significant upregulation in protein products for Reelin 410 and Reelin 180 kDa and downregulation for NMDA3B and RGS2 [25].
• The effect of palmitoylation on conformation of RGS2 was examined by monitoring spectra of the intrinsic fluorescence and Circular Dichroism [26].
• Our in situ hybridization results obtained on human embryonic and fetal ocular tissue sections constitute the first molecular histological data providing an explanation for the occurrence of precocious glaucoma in human patients affected by ARS caused by PITX2 mutations [27].
• In this study we investigated the effects of RGS2 on G protein modulation of recombinant P/Q-type channels expressed in a human embryonic kidney (HEK293) cell line using whole-cell recordings [28].

References