Protein degradation pathways
Our research interest lies in understanding how pathogenic proteins can be eliminated from the cells and their components recycled. In particular our research focuses on oncogenic protein degradation in relation to biology of cancer.
There are two major fundamentally different mechanisms by which cells degrade proteins for turnover and recycling purposes: the lysosome and the proteasome. Our research uses a creative combination of pharmacological, biochemical and genetic approaches to rigorously investigate the biological significance of these degradation mechanisms in normal and cancer cells.
Hence, our aim is to understand the complexity of various degradation systems and its explicit interactions and mechanisms, that might provide a foundation for the development of diagnostic strategies and major conceptual advance to uncover novel therapeutic drug targets in malignancies as well as in other human disorders.
Current research projects
Ubiquitin-Proteasome System (UPS) in Cancer
The Ubiquitin-Proteasome System (UPS) involves the targeting of polyubiquitination proteins for recognition and processing by the 26S proteasome, a multicatalytic enzyme complex that degrades the proteins, and recycles ubiquitin. The ubiquitylation process is carried out by three classes of enzymes; E1 (activating enzyme), E2 (conjugating enzyme) and E3 (ubiquitin ligase), as well as DUB (deubiquitinating enzymes).
Many proteasome target proteins include a broad array of regulatory proteins that play important roles in cell cycle progression, cell development and differentiation, DNA damage responses, and tumorgenesis. In addition, aberrations in the components of the ubiquitin proteasome pathway are commonly observed in many cancers. We are interested in understanding the role of UPS in cancer and to investigate the possibility of targeting different steps the ubiquitin-proteasome system for cancer treatment.
Autophagy Pathways in Cancer
Proteins destined for lysosomal degradation can reach the lysosome by a variety of means and autophagy is one regulated pathway of lysosomal degradation in mammalian cells. There are three main processes of autophagy; of which we are focusing on is macroautophagy and chaperone-mediated autophagy CMA.
Autophagy in Cancer:
Activation of autophagy, as one regulated pathway of lysosomal degradation, confers stress resistance and sustains cancer cell survival under adverse conditions. Moreover, activation of autophagy has been implicated in mediating resistance to existing anticancer therapy. However, the role of autophagy in cancer is complex and our aim is to investigate the impact of manipulating autophagy pathways to understand the contribution of factors and signaling that might regulate tumorigenesis and chemoresistance.
Chaperone-mediated Autophagy (CMA) in Cancer:
In a mammalian cell, chaperone-mediated autophagy (CMA) is one of the types of autophagy that is specific to breakdown of protein. Beyond its selectivity for proteins, another unique feature of this type of autophagy is that proteins are directly transported into the lysosome for degradation during CMA. Depending on which proteins are degraded by this pathway, CMA can perform various physiological and pathological functions. To date the role of CMA in cancer cells has remained obscure and the physiological importance of CMA in cancer is currently not defined. Therefore, our research intends to investigate the CMA pathway in depths both at cellular and organismal level, in order to explore the intriguing possible role of CMA in various human cancers.
|Merve Kacal||PhD student|
|Helin Norberg||Assistant professor, Research team leader|
USP10 regulates the stability of the EMT-transcription factor Slug/SNAI2.
Biochem. Biophys. Res. Commun. 2018 08;502(4):429-434
Resistant to Targeted Therapy - Aim for Metabolic Liabilities.
Theranostics 2018 ;8(7):2061-2063
Effect of Mutant p53 Proteins on Glycolysis and Mitochondrial Metabolism.
Mol. Cell. Biol. 2017 Dec;37(24):
Characterization of the Role of the Malate Dehydrogenases to Lung Tumor Cell Survival.
J Cancer 2017 ;8(11):2088-2096
PHGDH Defines a Metabolic Subtype in Lung Adenocarcinomas with Poor Prognosis.
Cell Rep 2017 06;19(11):2289-2303
Activation of chaperone-mediated autophagy as a potential anticancer therapy.
Autophagy 2015 ;11(12):2370-1
Degradation of HK2 by chaperone-mediated autophagy promotes metabolic catastrophe and cell death.
J. Cell Biol. 2015 Aug;210(5):705-16
Activation of necroptosis in multiple sclerosis.
Cell Rep 2015 Mar;10(11):1836-49
Pharmacologic agents targeting autophagy.
J. Clin. Invest. 2015 Jan;125(1):5-13
Chaperone-mediated autophagy degrades mutant p53.
Genes Dev. 2013 Aug;27(15):1718-30
Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity.
Mol. Cell 2013 Jan;49(2):331-8
Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13.
Cell 2011 Sep;147(1):223-34