̽����ѡ

Research description

My research group defines the biochemical and ̽����ѡ importance of the five enzymes that post-translationally modify so-called CAAX proteins. CAAX proteins, including K-RAS, RAC1, and prelamin A, are involved in the pathogenesis of both common and rare diseases such as cancer, inflammatory disorders, and accelerated aging syndromes (progeria). Over the past 20 years, we have defined the role of the five enzymes; studied how their activities influence disease development; and evaluated their suitability as targets for new therapies.

To accomplish this, we have used a broad spectrum of research platforms of molecular, translational, and epidemiologic character. With support from US, European, and Swedish grant agencies—and by us highly appreciated awards and recognition—we have been given unique opportunities to perform curiosity-driven basic research and resources to capitalize on unexpected results—both within and outside the CAAX-protein field. Here are two examples:

First, our group discovered—contrary to popular belief—that antioxidants including vitamin E and beta-carotene accelerate the progression and metastasis of lung cancer and malignant melanoma—driven by the CAAX-protein oncoproteins KRAS and NRAS. Molecular analyses led to the identification of a new mechanism that drives metastasis: the transcription factor BACH1 is activated in response to dietary antioxidants and by endogenous cellular antioxidants; BACH1 switches on the expression of glycolytic genes, which stimulates aerobic glycolysis which in turn fuels cancer cell invasion and metastasis.

Overall, these results provide a potential explanation for the varying outcomes of clinical trials with antioxidants and a therapeutic opportunity to prevent lung cancer metastasis. They have also led to interesting discussions on cancer prevention and nutritional recommendations for cancer patients.

Second, we identified a new potential therapy for children with Hutchinson-Gilford Progeria Syndrome (HGPS). A mutation in the CAAX-protein prelamin A (LMNA) causes HGPS which is associated with rapid aging (hair loss, muscle weakness, arthritis, and osteoporosis) and death in teenage years from cardiovascular disease. We found that targeting prelamin A methylation by inhibiting the enzyme ICMT markedly improves disease phenotypes and survival in mice with progeria and overcomes senescence of cultured cells from children with HGPS.

Our main challenge for the future is to synthesize potent and specific ICMT inhibitors which will form the basis for further development and clinical trials.

10 Selected publications

'
Kashif M, Yao H, Schmidt S, Chen X, Truong M, Tüksammel E, Liu Y, Bergo MO
Redox Biol 2023 Apr;60():102619

Chen X, Yao H, Kashif M, Revêchon G, Eriksson M, Hu J, Wang T, Liu Y, Tüksammel E, Strömblad S, Ahearn IM, Philips MR, Wiel C, Ibrahim MX, Bergo MO
Elife 2021 Feb;10():

Karlsson C, Akula MK, Staffas A, Cisowski J, Sayin VI, Ibrahim MX, Lindahl P, Bergo MO
Leukemia 2021 Feb;35(2):606-609

Yao H, Chen X, Kashif M, Wang T, Ibrahim MX, Tüksammel E, Revêchon G, Eriksson M, Wiel C, Bergo MO
Aging Cell 2020 Aug;19(8):e13200

Wiel C, Le Gal K, Ibrahim MX, Jahangir CA, Kashif M, Yao H, Ziegler DV, Xu X, Ghosh T, Mondal T, Kanduri C, Lindahl P, Sayin VI, Bergo MO
Cell 2019 Jul;178(2):330-345.e22

Akula MK, Ibrahim MX, Ivarsson EG, Khan OM, Kumar IT, Erlandsson M, Karlsson C, Xu X, Brisslert M, Brakebusch C, Wang D, Bokarewa M, Sayin VI, Bergo MO
Nat Commun 2019 Sep;10(1):3975

Le Gal K, Ibrahim MX, Wiel C, Sayin VI, Akula MK, Karlsson C, Dalin MG, Akyürek LM, Lindahl P, Nilsson J, Bergo MO
Sci Transl Med 2015 Oct;7(308):308re8

Sayin VI, Ibrahim MX, Larsson E, Nilsson JA, Lindahl P, Bergo MO
Sci Transl Med 2014 Jan;6(221):221ra15

Ibrahim MX, Sayin VI, Akula MK, Liu M, Fong LG, Young SG, Bergo MO
Science 2013 Jun;340(6138):1330-3

Khan OM, Akula MK, Skålen K, Karlsson C, Ståhlman M, Young SG, Borén J, Bergo MO
Circulation 2013 Feb;127(7):782-90

Teaching portfolio

I taught in the dental and ̽����ѡ programs as an “amanuens” and PhD student at Umeå University. At the University of Gothenburg, I taught cell biology at the BMA program and also served in the Committee for Research Education at the University of Gothenburg during a period of extensive reorganization of the eligibility, scope, topics, courses, and financing of research education at the Sahlgrenska Academy. As a docent and professor, I mainly focused on teaching at masters and doctoral levels and have been main supervisor for 9 completed PhD students.

Another rewarding education-related experience is as a popular science lecturer to patient organizations, oncologists, nutritionists, dieticians, and the general public. Finally, I have 10 years of experience as chairman of the board for Folkuniversitetet väst where we focus on life-long learning and educational activities for all ages (such as folkbildning, schools for art, dance, and acting, and SFI, Komvux, Korta vägen, folkhögskolor, and gymnasier). I have thus gained a broad experience with education in Swedish society.

Contact

View a video