Protein homeostasis in cancer
Head: Petr Müller
Brno node
HOME INSTITUTION
Masaryk Memorial Cancer Institute
RESEARCH PROGRAMME(S)
RP 1 - Molecular basis of cancer and molecular targets
RP 2 - Research and development of anticancer pharmaceuticals and therapeutic methods
Out of chaos comes order: Understanding proteotoxic stress in cancer in cancer.
- Mission: Understanding tumor adaptation to proteotoxic stress and identifying novel therapeutic targets leveraging proteostatic mechanisms.
An important characteristic of a tumor cell is its high demands on maintaining protein homeostasis. Genome instability, high frequency of mutations and increased proteosynthesis lead to activation of stress signaling and increased production of chaperones on which tumor cells become dependent. The goal of our research program is to analyze mechanisms leading to activation of the stress response in tumors, to describe mechanisms leading to hyperactivation of chaperones and to identify new targets suitable for antitumor therapy.
SELECTED PUBLICATIONS
- Durech M, Trcka F, Man P, Blackburn EA, Hernychova L, Dvorakova P, Coufalova D, Kavan D, Vojtesek B, Muller P. Novel Entropically Driven Conformation-specific Interactions with Tomm34 Protein Modulate Hsp70 Protein Folding and ATPase Activities. Mol Cell Proteomics. 2016 May;15(5):1710-27. DOI: 10.1074/mcp.M116.058131
- Krejci A, Hupp TR, Lexa M, Vojtesek B, Muller P. Hammock: a hidden Markov model-based peptide clustering algorithm to identify protein-interaction consensus motifs in large datasets. Bioinformatics. 2016 Jan 1;32(1):9-16. DOI: 10.1093/bioinformatics/btv522
- Mistrik M, Skrott Z, Muller P, Panacek A, Hochvaldova L, Chroma K, Buchtova T, Vandova V, Kvitek L, Bartek J. Microthermal-induced subcellular-targeted protein damage in cells on plasmonic nanosilver-modified surfaces evokes a two-phase HSP-p97/VCP response. Nat Commun. 2021 Jan 29;12(1):713. DOI: 10.1038/s41467-021-20989-9
- Muller P, Ruckova E, Halada P, Coates PJ, Hrstka R, Lane DP, Vojtesek B. C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to co-chaperones CHIP and HOP to determine cellular protein folding/degradation balances. Oncogene. 2013 Jun 20;32(25):3101-10. DOI: 10.1038/onc.2012.314
- Trcka F, Durech M, Vankova P, Vandova V, Simoncik O, Kavan D, Vojtesek B, Muller P, Man P. The interaction of the mitochondrial protein importer TOMM34 with HSP70 is regulated by TOMM34 phosphorylation and binding to 14-3-3 adaptors. J Biol Chem. 2020 Jul 3;295(27):8928-8944. DOI: 10.1074/jbc.RA120.012624
COLLABORATION WITHIN THE NICR
SPECIALIZED EXPERTISE AND TECHNOLOGY
Methodological approaches for protein studies including: production and purification of recombinant proteins, study of protein complexes using functional proteomics and structural proteomics using hydrogen-deuterium exchange (HDX)
Synthetic biology applied in the creation of stable cell models using lentiviral expression vectors and PiggyBac transposons; manipulation of gene expression using gene knockouts or inducible gene expression
Production, characterization and modification of monoclonal antibodies using: phage display technology, epitope analysis, antibody conjugation with fluorochromes, small molecules or enzymes
Stress response analysis in cancer cells at the mRNA, protein and cell level using omic methods, life-cell imaging or flow cytometry
COLLABORATION WITH LARGE RESEARCH INFRASTRUCTURES AND RESEARCH CENTRES
Network of Czech Biobanks BBMRI.cz
National infrastructure for biological and biomedical imaging Czech-Bioimaging
Central European Institute of Technology at Masaryk University CEITEC MU