Eya4 Induces Hypertrophy via Regulation of p27 ^kip1

Abstract

Background-E193, a heterozygous truncating mutation in the human transcription cofactor Eyes absent 4 (Eya4), causes hearing impairment followed by dilative cardiomyopathy. Methods and Results-In this study, we first show Eya4 and E193 alter the expression of p27 kip1 in vitro, suggesting Eya4 is a negative regulator of p27. Next, we generated transgenic mice with cardiac-specific overexpression of Eya4 or E193. Luciferase and chromatin immunoprecipitation assays confirmed Eya4 and E193 bind and regulate p27 expression in a contradictory manner. Activity and phosphorylation status of the downstream molecules casein kinase-2α and histone deacetylase 2 were significantly elevated in Eya4-but significantly reduced in E193-overexpressing animals compared with wild-type littermates. Magnetic resonance imaging and hemodynamic analysis indicate Eya4-overexpression results in an age-dependent development of hypertrophy already under baseline conditions with no obvious functional effects, whereas E193 animals develop onset of dilative cardiomyopathy as seen in human E193 patients. Both cardiac phenotypes were aggravated on pressure overload. Finally, we identified a new heterozygous truncating Eya4 mutation, E215, which leads to similar clinical features of disease and a stable myocardial expression of the mutant protein as seen with E193. Conclusions-Our

EYA4 Promotes Cell Proliferation Through Downregulation of p27Kip1 in Glioma

“…Our data suggest that Six1 is required for the ability of EYA4 to suppress the expression of p27Kip1 in glioma cells (Fig. 7), which is in line with previous reports that Eya4/Six1 regulates normal cardiac function through regulation of p27Kip1 [43].…”

“…Studies have shown that EYA4 interacts with Six1 to form a bipartite transcription factor essential for the regulation of various downstream targets expression [34,43,44]. The transcription co-activator EYA4 could be recruited in the context of local chromatin; however, it lacks intrinsic DNA-binding activity.…”

Identification of candidate biomarkers and pathways associated with type 1 diabetes mellitus using bioinformatics analysis

“…Expression of ERRFI1 190 , ALOX12 191 , SOCS5 192 , DDIT4 193 , DUSP4 194 , IL6ST 195 , DUSP1 196 , SMAD1 197 , NCL (nucleolin) 198 , METTL14 199 , FMOD (fibromodulin) 200 , CYGB (cytoglobin) 201 , UNC5A 202 and TAAR9 203 are believed to be associated with diabetic nephropathy. Genes include FAP (fibroblast activation protein alpha) 204 , EYA4 205 , BCL9 206 , IRF2BP2 207 , EGR3 208 , GADD45B 209 , DMD (dystrophin) 210 , LSR (lipolysis stimulated lipoprotein receptor) 211 , DLL4 212 , SUN2 213 , SOS1 214 , PIK3CA 215 , GAMT (guanidinoacetate N -methyltransferase) 216 , RBM47 217 , HSP90AA1 218 , GAB1 219 , S1PR1 220 , EDNRB (endothelin receptor type B) 221 , NFKBIA (NFKB inhibitor alpha) 222 , GJA1 223 , GADD45G 224 , PHLDA1 225 , CMPK2 226 , FIGN (fidgetin, microtubule severing factor) 227 , KCNJ2 228 , ABCC9 229 , DIRAS3 230 , EPHX1 231 , RAB4A 232 , UBIAD1 233 , CASQ2 234 , TTN (titin) 235 , KCNH1 236 , JPH2 237 , OXGR1 238 , UCHL1 239 , SERPINA3 240 , MMP28 241 , ADAMTS2 242 , P2RY1 243 , CSF2RA 244 , MYO1F …”

Inducible over‐expression of cardiac Nos1ap causes short QT syndrome in transgenic mice

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