ABSTRACT
Peroxisome proliferator-activated receptor gamma (PPARgamma) belongs to a nuclear receptor superfamily; members of which play key roles in the control of body metabolism principally by acting on adipose tissue. Ligands of PPARgamma, such as thiazolidinediones, are widely used in the treatment of metabolic syndromes and type 2 diabetes mellitus (T2DM). Although these drugs have potential benefits in the treatment of T2DM, they also cause unwanted side effects. Thus, understanding the molecular mechanisms governing the transcriptional activity of PPARgamma is of prime importance in the development of new selective drugs or drugs with fewer side effects. Recent advancements in molecular biology have made it possible to obtain a deeper understanding of the role of PPARgamma in body homeostasis. The transcriptional activity of PPARgamma is subject to regulation either by interacting proteins or by modification of the protein itself. New interacting partners of PPARgamma with new functions are being unveiled. In addition, post-translational modification by various cellular signals contributes to fine-tuning of the transcriptional activities of PPARgamma. In this review, we will summarize recent advancements in our understanding of the post-translational modifications of, and proteins interacting with, PPARgamma, both of which affect its transcriptional activities in relation to adipogenesis.
Subject(s)
Gene Expression Regulation , Homeostasis , Models, Genetic , PPAR gamma/genetics , Protein Processing, Post-Translational , Sumoylation , Transcription Factors/metabolism , UbiquitinationABSTRACT
Small ubiquitin-like modifiers (SUMO) are a family of proteins that modulate important functional properties,including protein interaction,subcellular localization,protein dimerization,DNA binding and/or transactivation of transcription factors.It has been suggested that SUMO proteins may play an important role in breast carcinogenesis by sumoylation of estrogen signaling proteins such as co-regulators,and breast cancer-related proteins.
ABSTRACT
Resistance to thyroid hormone (RTH) is a rare disorder characterized by variable tissue hyporesponsiveness to thyroid hormone, usually caused by mutations in the thyroid hormone receptor beta (TRβ). We describe a large Brazilian family harboring a novel mutation affecting TRβ gene and inducing RTH. A 14-year-old girl was found to have elevated free T4 and free T3 plasma concentrations in coexistence with unsuppressed TSH and a questionable goiter. The diagnosis of RTH was verified by identification of a novel mutation (I431V) in the TRβ gene. Sixteen asymptomatic relatives of the proposita are also affected by the mutation. Functional studies showed that I431V mutation exerts dominant-negative effect on wild type TRβ, mainly by impairment of ligand-dependent release of corepressor SMRT. The presence of this mutation reduces potency, but does not affect efficacy of thyroid hormone action, in accordance with the clinical picture of eumetabolism of the affected individuals.
A resistência ao hormônio tireoideano (RHT) é uma doença rara, causada por variável hiporresponsividade dos tecidos aos hormônios tireoideanos, usualmente causada por mutações no receptor beta do hormônio tireoideano (TRβ). Descrevemos uma grande família brasileira portadora de uma nova mutação afetando o gene do TRβ, induzindo RHT. Uma paciente de 14 anos de idade apresentou concentrações plasmáticas elevadas de T4 e T3 livres, associadas a TSH não-suprimido e bócio questionável. O diagnóstico de RHT foi estabelecido pela identificação da mutação I431V no gene do TRβ. Dezesseis parentes assintomáticos da probanda também são afetados pela mutação. Estudos funcionais mostram que a mutação I431V exerce efeito dominante negativo sobre o TR selvagem, basicamente, por prejudicar a liberação do correpressor SMRT ligante-dependente. A presença desta mutação reduz a potência, mas não afeta a eficácia da ação do hormônio tireoideano, o que está de acordo com a apresentação clínica de eumetabolismo dos indivíduos afetados.