title: Nuclear MEK1 sequesters PPARγ and bisects MEK1/ERK signaling: a non-canonical pathway of retinoic acid inhibition of adipocyte differentiation.
abstract: Uncontrolled adipogenesis and adipocyte proliferation have been connected to human comorbidities. Retinoic acid (RA) is known to inhibit adipocyte differentiation, however the underlying mechanisms have not been adequately understood. This study reports that RA acting as a ligand to RA receptors (RARs and RXRs) is not a sine qua non to the inhibition of adipogenesis. Our intriguing observation of a negative correlation between increased retinoylation and adipogenesis led us to explore retinoylated proteins in adipocytes. Exportin (CRM1) was found to be retinoylated, which in turn can affect the spatio-temporal regulation of the important signaling molecule mitogen-activated protein kinase kinase 1 (MEK1), likely by disrupting its export from the nucleus. Nuclear enrichment of MEK1 physically sequesters peroxisome proliferator-activated receptor gamma (PPARγ), the master regulator of adipogenesis, from its target genes and thus inhibits adipogenesis while also disrupting the MEK1-extracellular-signal regulated kinase (ERK) signaling cascade. This study is first to report the inhibition of adipocyte differentiation by retinoylation.
authors: CSIR-Institute of Microbial Technology, Chandigarh, India.
authors: Sandeep
authors: S
authors: Dave
authors: CSIR-Institute of Microbial Technology, Chandigarh, India.
authors: Ravikanth
authors: R
authors: Nanduri
authors: CSIR-Institute of Microbial Technology, Chandigarh, India.
authors: Hedwin Kitdorlang
authors: HK
authors: Dkhar
authors: CSIR-Institute of Microbial Technology, Chandigarh, India.
authors: Ella
authors: E
authors: Bhagyaraj
authors: CSIR-Institute of Microbial Technology, Chandigarh, India.
authors: Alka
authors: A
authors: Rao
authors: CSIR-Institute of Microbial Technology, Chandigarh, India.
authors: Pawan
authors: P
authors: Gupta
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D050156:Adipogenesis; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D028884:Karyopherins / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism / Q000502:physiology*; D020935:MAP Kinase Signaling System; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism* / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism / Q000502:physiology*; D000097606:Exportin 1 Protein
chemical_list: D028884:Karyopherins; D048369:MAP Kinase Kinase 1; D047495:PPAR gamma; D018160:Receptors, Cytoplasmic and Nuclear; D014212:Tretinoin; D000097606:Exportin 1 Protein; C482127:Map2k1 protein, mouse