Helin V. Norberg

Ragnar Söderbergforskare i medicin // År: 2015 //
Anslagsförvaltare: Karolinska Institutet // Belopp: 8 000 000 kr

Min forskning

Kan cellens naturliga autofagi utnyttjas i  cancerbehandling?

Helin Vakifahmetoglu Norbergs forskning fokuserar på autofagi som är en naturlig process för nedbrytning av cellkomponenter. Målet är att ta reda på autofagis roll vid cancer – vilket skulle kunna öppna nya möjligheter för både diagnos och behandling.

Helin Vakifahmetoglu Norberg undersöker chaperon-medierad autofagi (CMA), som är en naturlig process för nedbrytning av cellkomponenter. I sitt forskningsprojekt vill hon fastställa vilka proteiner som specifikt bryts ner vid CMA, både normalt och vid sjukdomstillstånd.

CMA har visat sig vara en viktig komponent när sjukdomar som Parkinson och Alzheimers utvecklas. Helin vill undersöka vilken betydelse processen har vid cancer, och har redan visat att aktivering av CMA leder till att cancerceller dör medan normala celler överlever. Därför vill hon ta reda på om det går att aktivera CMA som en ny behandlingsstrategi.

Research

The goal of our research is to characterize the protein profile that is specifically degraded through chaperone-mediated autophagy (CMA) to understand the role of CMA in normal and pathological conditions and to investigate the possibility to selectively activate the CMA pathway as a novel therapeutic strategy. CMA is a highly selective process that involves the lysosomal degradation of proteins. Beyond its physiological significance, CMA is associated with various human disorders. Despite this fact, identification of CMA substrates and its physiological role is much less studied.

Previously, we identified a small molecule inhibitor, spautin-1 (Liu et al., Cell 2011), which stimulate the degradation of mutant proteins by activating CMA (Vakifahmetoglu-Norberg et al., Genes Dev 2013). Furthermore, our studies show that the CMA activation induces the death of cancer cells, through the degradation of oncogenic proteins, while normal cells are spared (Xia et al., resubmitted to J Cell Biol 2015). These findings provide a rationale for further exploring of the CMA pathway. Spautins may represent the first-in-class by pharmacological means to induce CMA and I propose that selective CMA activation may be considered as a novel therapeutic strategy for the removal of pathological mutant proteins. Taken advantage of pharmacological, biochemical and genetic approaches I will rigorously investigate this possibility and study the therapeutic potential of CMA in human disorders.

Publikationer i urval

1. Xia X, Najafov A, Geng J, Han X, Galan-Acosta L, Shan B, Zhang, Norberg N, Zhang, Pan L, Liu, Coloff JL, Ofengeim D, Zhu H, Wu, Cai, Yates J, Yuan J and Vakifahmetoglu-Norberg H. Degradation of HK2 by Chaperone-Mediated Autophagy promotes Metabolic Catastrophe and Cell Death. Journal of Cell Biology, MS:201503044, resubmitted, process of Acceptance IF. 9.8

2. Ofengeim D, Ito Y, Najafov A, Zhang Y, Shan B, DeWitt JP, Ye J, Zhang X, Chang A, Vakifahmetoglu-Norberg H, Geng J, Py B, Zhou W, Amin P, Berlink Lima J, Qi C, Yu Q, Trapp B and Yuan J. Activation of Necroptosis in Multiple Sclerosis. Cell Reports. 2015 Mar;17. pii: S2211-1247(15)00209-0. doi: 10.1016/j.celrep.2015.02.051. IF 7.2

3. Vakifahmetoglu-Norberg H, Xia HG, Yuan J. Pharmacologic agents targeting autophagy. J Clin Invest. 2015 Jan;125(1):5-13. doi: 10.1172/JCI73937. IF 14.6

4. Vakifahmetoglu-Norberg H1 , Norberg E, Perdomo AB, Olsson M, Ciccosanti F, Orrenius S, Fimia GM, Piacentini M, Zhivotovsky B. Caspase-2 promotes Cytoskeleton Protein Degradation during Apoptotic Cell Death. Cell Death Dis. 2013 Dec 5;4:e940. IF 5.17 1 (Corresponding author)

5. Vakifahmetoglu-Norberg H and Yuan J. A degradative detour for mutant p53. Autophagy. 2013 Dec;9(12):2158-60. IF 11.4

6. Vakifahmetoglu-Norberg H, Kim M, Xia HG, Iwanicki MP, Ofengeim D, Coloff JL, Pan L, Ince TA, Kroemer G, Brugge JS, Yuan J. Chaperone-mediated Autophagy degrades mutant p53. Genes Dev. 2013 Aug 1;27(15):1718-30. IF 12.64

7. Melas PA, Lennartsson A, Vakifahmetoglu-Norberg H, Wei Y, Åberg E, Werme M, Rogdaki M, Mannervik M, Wegener G, Brené S, Mathé AA, Lavebratt C. Allele-specific programming of Npy and epigenetic effects of physical activity in a genetic model of depression. Transl Psychiatry. 2013 May 7;3:e255. doi: 10.1038/tp.2013.31. IF 4.36

8. Py BF, Kim M, Vakifahmetoglu-Norberg H, Yuan J. NLRP3 deubiquitination by BRCC3 critically regulates the inflammasome activity. Molecular Cell. 2013 Jan 24;49(2):331-8. IF 14.46

9. Yi CH, Vakifahmetoglu-Norberg H, Yuan J. Integration of Apoptosis and Metabolism. Cold Spring Harb Symp Quant Biol. 2011;76:375-87. Nov 16.

10. Liu J, Xia H, Kim M, Xu L, Li Y, Zhang L, Cai Y, Norberg HV, Zhang T, Furuya T, Jin M, Zhu Z, Wang H, Yu J, Li Y, Hao Y, Choi A, Ke H, Ma D, Yuan J. Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell. 2011 Sep 30;147(1):223-34. IF 33.12