Augmentation of PPARγ-TAZ interaction contributes to the anti-adipogenic activity of KR62980

Polycystin-1 interacts with TAZ to stimulate osteoblastogenesis and inhibit adipogenesis

“…This schema proposes that mechanical forces, such as ECM stiffness, flow, and mechanical stretch, activate the PC1/PC2 complex (13,31,50,51,(63)(64)(65)(66), leading to stimulation of intracellular calcium, induction of PC1-CTT cleavage, and TAZ nuclear translocation to enhance Runx2-mediated induction of osteoblast gene transcription and to inhibit PPARγ and adipogenesis (33,39,42,44,46,67). Together this work identifies a new mechanosensing complex and the feasibility of targeting this complex for treating disorders caused by mechanical unloading and ageing.…”

“…TAZ also differentially regulates osteoblastogenesis and adipogenesis (42). Nuclear translocation of TAZ coactivates Runx2 to stimulate osteoblastogenesis (43) and represses PPARγ to inhibit adipogenesis (44) in vitro. Moreover, transgenic overexpression of Taz in osteoblasts leads to increased osteoblast-mediated bone formation and decreased bone marrow adipogenesis (45); depletion of taz in zebrafish impairs bone development (42), and Taz -/-mice have small stature and ossification defects (36).…”

“…Next, we examined whether the PC1-CTT/TAZ complex coregulates Runx2 and PPARγ activities (33,42). It is known that the PC1-CTT binds to TAZ, which is a coactivator for Runx2 and a corepressor for PPARγ activity (42,44), but the effects of the PC1-CTT/TAZ complex on Runx2 and PPARγ activities have not been studied. Thus, we overexpressed FLAG-tagged TAZ, PC1-CTT, and Runx2 or Pparg in HEK-293T cells and performed co-IP with an anti-FLAG antibody ( Figure 4, A and B).…”

Nuclear Receptors and Their Selective Pharmacologic Modulators

“…KR-62980 increased transiently expressed TAZ nuclear localization in Cos7 cells. It also increased the interaction of TAZ and PPARg in an immunoprecipitation assay using 3T3-L1 adipocytes, and decreased binding of PPRE containing DNA to PPARg in 3T3-L1 adipocyte nuclear protein extract (Jung et al, 2009). An abstract from the American Society for Bone and Mineral Research reported that KR-62980 has pro-bone-formation effects and helped maintain bone mass in ovariectomized mice (Bae et al, 2007).…”

“…Interestingly, pioglitazone significantly reduced the risk of breast cancer in the PROactive Trial (Dormandy et al, 2005). Further investigation into the antiadipogenic mechanism of KR-62980 revealed that TAZ (transcriptional coactivator with PDZ-binding motif) is necessary for KR-62980 to block rosiglitazone-induced adipocyte differentiation in 3T3-L1 cells (Jung et al, 2009). TAZ had been previously shown to bind PPARg and to function to block adipocyte and induce osteoblast differentiation from mesenchymal stem cells (Hong et al, 2005).…”