Browsing by Subject "HSP90"

Sort by: Order: Results:

Now showing items 1-3 of 3
  • Gungor, Burcin; Vanharanta, Lauri; Hölttä-Vuori, Maarit; Pirhonen, Juho; Petersen, Nikolaj H. T.; Gramolelli, Silvia; Ojala, Päivi M.; Kirkegaard, Thomas; Ikonen, Elina (2019)
    Objective: Heat Shock Proteins (HSPs) maintain cellular homeostasis under stress. HSP70 represents a major stress-inducible family member and has been identified as a druggable target in inherited cholesterol-sphingolipid storage diseases. We investigated if HSP70 modulates cholesterol accumulation in more common conditions related to atherogenesis. Methods: We studied the effects of recombinant HSP70 in cholesterol-laden primary macrophages from human blood donors and pharmacological HSP70 upregulation in high-cholesterol diet fed zebrafish. Results: Recombinant HSP70 facilitated cholesterol removal from primary human macrophage foam cells. RNA sequencing revealed that HSP70 induced a robust transcriptional re-programming, including upregulation of key targets of liver X receptors (LXR), master regulators of whole-body cholesterol removal. Mechanistically, HSP70 interacted with the macrophage LXRalpha promoter, increased LXRalpha and its target mRNAs, and led to elevated levels of key proteins facilitating cholesterol efflux, including ATP-binding cassette transporters A1 and G1. Pharmacological augmentation of endogenous HSP70 in high-cholesterol diet fed zebrafish activated LXR and its target mRNAs and reduced cholesterol storage at the whole organism level. Conclusion: These data demonstrate that HSP70 exerts a cholesterol lowering effect in primary human cells and animals and uncover a nuclear action of HSP70 in mediating cross-talk between HSP and LXR transcriptional regulation. (C) 2019 The Authors. Published by Elsevier GmbH.
  • Duarte, Gustavo Turqueto; Pandey, Prashant K.; Vaid, Neha; Alseekh, Saleh; Fernie, Alisdair R.; Nikoloski, Zoran; Laitinen, Roosa A. E. (2021)
    Nitrogen (N) is fundamental to plant growth, development and yield. Genes underlying N utilization and assimilation are well-characterized, but mechanisms underpinning plasticity of different phenotypes in response to N remain elusive. Here, using Arabidopsis thaliana accessions, we dissected the genetic architecture of plasticity in early and late rosette diameter, flowering time and yield, in response to three levels of N in the soil. Furthermore, we found that the plasticity in levels of primary metabolites were related with the plasticities of the studied traits. Genome-wide association analysis identified three significant associations for phenotypic plasticity, one for early rosette diameter and two for flowering time. We confirmed that the gene At1g19880, hereafter named as PLASTICITY OF ROSETTE TO NITROGEN 1 (PROTON1), encoding for a regulator of chromatin condensation 1 (RCC1) family protein, conferred plasticity of rosette diameter in response to N. Treatment of PROTON1 T-DNA line with salt implied that the reduced plasticity of early rosette diameter was not a general growth response to stress. We further showed that plasticities of growth and flowering-related traits differed between environmental cues, indicating decoupled genetic programs regulating these traits. Our findings provide a prospective to identify genes that stabilize performance under fluctuating environments.
  • Grbovic-Huezo, Olivera; Pitter, Kenneth; Lecomte, Nicolas; Saglimbeni, Joseph; Askan, Gokce; Holm, Matilda; Melchor, Jerry; Chandwani, Rohit; Joshi, Suhasini; Haglund, Caj; Iacobuzio-Donahue, Christine; Chiosis, Gabriela; Tammela, Tuomas; Leach, Steven (2020)