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Group Martin Bergö

Research Summary

Our goal is to define the biochemical and medical importance of the posttranslational processing of CAAX proteins—including K-RAS and prelamin A—and to define the suitability of the CAAX protein processing enzymes as therapeutic targets for the treatment of cancer and other diseases.
The CAAX proteins undergo three posttranslational processing steps: prenylation, endoproteolysis, and methylation. These processing steps are mediated by five different enzymes (FTase, GGTase-I, RCE1, ZMPSTE24, ICMT) and render the carboxyl terminus of CAAX proteins hydrophobic stimulating interactions with membranes and effector proteins.
Mutations in the RAS proteins deregulate cell growth and are involved in the pathogenesis of cancer, such as lung-, colon, and pancreatic cancer and myeloid leukemia. Mutations in prelamin A causes Hutchinson-Gilford progeria syndrome – a pediatric syndrome associated with misshaped cell nuclei and a host of aging-like disease phenotypes. One strategy to render the mutant K-RAS and prelamin A less harmful is to interfere with their ability to bind to membrane surfaces (e.g., plasma membrane and nuclear envelope). This could be accomplished by inhibiting the enzymes that modify the CAAX motif.
We use genetic strategies in mice to understand the importance of the CAAX protein processing enzymes for cellular transformation and the development of solid and hematopoietic tumors induced by mutations in RAS and RAF proteins and the neurofibromatosis 1 gene (NF1), and for the development of progeria induced by prelamin A accumulation. We also attempt to define the biochemical consequences of CAAX protein processing for protein–protein interactions, membrane association, and protein stability.

Research Tools and Resources

We use a range of molecular and cellular biology techniques in mouse and human cells and mouse models and genetic strategies to define mechanisms and treatment of human diseases using conditional and conventional knockout and transgenic mice.

Current Group Members

Martin Bergö, PhD, Professor
Christin Karlsson, PhD
Tingting Wu, MD/PhD
Jaroslaw Cisowski, PhD
Clotilde Wiel, PhD
Martin Dalin, MD/PhD
Omar Khan, PhD
Mohamed Ibrahim, PhD
Volkan Sayin, PhD
Murali Akula, PhD student
Kristell le Gal Beneroso, PhD student
Emil Ivarsson, PhD student
Ella Äng, MD, PhD student
Tony Zou, PhD student

Selected Publications

(IF = impact factor)

  1. Cisowski J, Sayin VI, Liu M, Karlsson C, and Bergo MO. (2015) Oncogene-induced senescence underlies the mutual exclusive nature of oncogenic KRAS and BRAF. Oncogene (In press) IF8.6
  2. Staffas A, Staffas A, Karlsson C, Persson M, Palmqvist P, and Bergo MO. (2015) Wild-type KRAS inhibits oncogenic KRAS-induced T-ALL in mice. Leukemia (In press) IF10
  3. Sayin VI, Ibrahim MX, Larsson E, Nilsson JA, Lindahl P, and Bergo MO. (2014) Antioxidants accelerate lung cancer progression in mice. Science Transl. Med. 6: 221ra15. IF14
  4. Ibrahim MX, Sayin VI, Akula MK, Liu M, Fong LG, Young SG, and Bergo MO. (2013) Targeting isoprenylcysteine methylation improves disease phenotypes in a mouse model of accelerated aging. Science 340: 1330–1333. IF31
  5. Khan O, Krishna M, Akula MK, Skalen K, Karlsson C, Ståhlman M, Young SG, Borén J, and Bergo MO. (2013) Targeting GGTase-I activates RHOA, increases macrophage reverse cholesterol transport, and reduces atherosclerosis in mice. Circulation 127: 782–790. IF15

 

PubMed

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