Associate Professor of Exp Pathology and senior researcher in Prof. Jiri Bartek group at MBB Dept, Sci Life Lab, Karolinska Institutet in Stockholm.
Cell phone: +46 (0) 709989566
MSc, Biomedicine, 1999, Karolinska Institutet, Stockholm, Sweden
PhD, Oncology-Experimental Oncology, 2004, Karolinska Institutet, Stockholm, Sweden
Docent, Experimental Pathology, 2012, Karolinska Institutet, Stockholm, Sweden
Our main goal is to understand the regulation of ribosome biogenesis in human cancer cells and how it is different from normal cells. The objectives of our studies are to identify and characterize proteins that are involved in ribosome biogenesis surveillance through the p53 tumor suppressor pathway, to better define and understand functions of the nucleolar histone chaperone NPM1, and finally to explore novel concepts related to the emerging "ribosome code" as it applies to cancer, especially glioma.
Cancer cells display several abnormal properties known as hallmarks including increased growth and proliferation. Better knowledge about cellular growth control will help to develop strategies for therapeutic intervention targeting aberrant cancer cell growth. How does a cell control its own growth - that is increase in biomass? Ribosomes are intracellular factories made up of large RNA species and around 80 ribosomal proteins and that synthesize proteins thus being essential for cell growth. The production of ribosomes, ribosome biogenesis, is one of the most energy-consuming processes in the cell and must be closely controlled. Ribosome biogenesis has been studied mainly in yeast and bacteria, but the mechanisms and control systems involved are still largely unexplored in mammalian cells. A deficiency in ribosome biogenesis triggers a cellular stress response that t least in part dependent on ribosomal protein L11 and L5 that signals to the tumor suppressor p53. One of our long-term goals is to further unravel the principles of ribosome biogenesis surveillance and to understand the dynamics and the finer details of the p53 pathway in sensing ribosome dysfunction. In fact, activation of the p53 anti-proliferative cellular response to ribosome loss could be used to our advantage in cancer therapy, and to this end, we are also evaluating novel combinations of small molecules that are inhibiting ribosome biogenesis. Cancer cells need a higher or altered protein synthesis in order to sustain their rapid growth. Changes in specific mRNA translation patterns may account for some of the changes seen in cancer cells but perhaps of equal importance are alterations in the ribosome itself. Are ribosomes made with a modification code in analogy with the histone code and that is in control of mRNA translation patterns?
The nucleolus is the site for ribosome biogenesis and if we want to understand the dynamics of ribosome production we should also study the nucleolus. The process of ribosome biogenesis in the nucleolus may be seen as a paradigm for understanding of how changes in chromatin are linked to a specific cell function. We are investigating how the structure and function of the nucleolus change during cell differentiation, cell stress and how it is different in cancer cells. We aim to understand how the structure of the surrounding nucleolar chromatin is adapting to changes in cellular growth demand and thereby control ribosome biogenesis and vice versa.
A key regulator of nucleolar structure is NPM1 (also known as nucleophosmin) a nucleolar histone chaperone and we are currently re-visiting the pleiotropic functions of NPM1 in genome stability, ribosome biogenesis, nucleolar structure and perinucleolar heterochromatin architecture.
For a complete list see Researchgate or use Pubmed string “Lindstrom MS”.
Role of ribosomal protein mutations in tumor development (Review).
Int. J. Oncol. 2016 Apr;48(4):1313-24
mTOR inhibitors blunt the p53 response to nucleolar stress by regulating RPL11 and MDM2 levels.
Cancer Biol. Ther. 2014 ;15(11):1499-514
Loss of nucleolar histone chaperone NPM1 triggers rearrangement of heterochromatin and synergizes with a deficiency in DNA methyltransferase DNMT3A to drive ribosomal DNA transcription.
J. Biol. Chem. 2014 Dec;289(50):34601-19
Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53.
Genes Dev. 2014 Jan;28(1):58-70
Brain abnormalities and glioma-like lesions in mice overexpressing the long isoform of PDGF-A in astrocytic cells.
PLoS ONE 2011 Apr;6(4):e18303
An ARF-independent c-MYC-activated tumor suppression pathway mediated by ribosomal protein-Mdm2 Interaction.
Cancer Cell 2010 Sep;18(3):231-43
Ribosomal protein S9 is a novel B23/NPM-binding protein required for normal cell proliferation.
J. Biol. Chem. 2008 Jun;283(23):15568-76
Cancer-associated mutations in the MDM2 zinc finger domain disrupt ribosomal protein interaction and attenuate MDM2-induced p53 degradation.
Mol. Cell. Biol. 2007 Feb;27(3):1056-68
Myc and E2F1 induce p53 through p14ARF-independent mechanisms in human fibroblasts.
Oncogene 2003 Aug;22(32):4993-5005
p14ARF homozygous deletion or MDM2 overexpression in Burkitt lymphoma lines carrying wild type p53.
Oncogene 2001 Apr;20(17):2171-7
Transcription factor PROX1: its role in development and cancer
Cancer metastasis reviews 2012;31(3-4):793-805
Novel Perspectives on p53 Function in Neural Stem Cells and Brain Tumors
Journal of oncology 2011;2011():852970-
NPM1/B23: A Multifunctional Chaperone in Ribosome Biogenesis and Chromatin Remodeling
Biochemistry research international 2011;2011():195209-
PROX1 is a predictor of survival for gliomas WHO grade II
BRITISH JOURNAL OF CANCER 2011;104(11):1747-54
Uncoupling of the ER alpha regulated morphological phenotype from the cancer stem cell phenotype in human breast cancer cell lines
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2011;405(4):581-7
An ARF-Independent c-MYC-Activated Tumor Suppression Pathway Mediated by Ribosomal Protein-Mdm2 Interaction
CANCER CELL 2010;18(3):231-43
Expression of PROX1 Is a Common Feature of High-Grade Malignant Astrocytic Gliomas
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY 2010;69(2):129-38
PROX1 IS A PREDICTOR OF SURVIVAL FOR ASTROCYTIC GLIOMAS BUT NOT FOR OLIGODENDROGLIOMAS GRADE II
Emerging functions of ribosomal proteins in gene-specific transcription and translation
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2009;379(2):167-70
Ribosomal protein S9 is a novel B23/NPM-binding protein required for normal cell proliferation
JOURNAL OF BIOLOGICAL CHEMISTRY 2008;283(23):15568-76
Cancer-associated mutations in the MDM2 zinc finger domain disrupt ribosomal protein interaction and attenuate MDM2-induced p53 degradation
MOLECULAR AND CELLULAR BIOLOGY 2007;27(3):1056-68
Putting a finger on growth surveillance - Insight into MDM2 zinc finger-ribosomal protein interactions
CELL CYCLE 2007;6(4):434-7
B23 and ARF - Friends or foes?
CELL BIOCHEMISTRY AND BIOPHYSICS 2006;46(1):79-90
Essential role of the B23/NPM core domain in regulating ARF binding and B23 stability
JOURNAL OF BIOLOGICAL CHEMISTRY 2006;281(27):18463-72
p16(INK4a) and laminin-5 gamma 2 chain expression during the progression of cervical neoplasia
ACTA ONCOLOGICA 2006;45(6):676-84
p16INK4A and p14ARF expression pattern by immunohistochemistry in human papillomavirus-related cervical neoplasia
MODERN PATHOLOGY 2005;18(5):629-37
Predictive significance of the alterations of p16INK4A, p14ARF, p53, and proliferating cell nuclear antigen expression in the progression of cervical cancer
CLINICAL CANCER RESEARCH 2004;10(7):2407-14
Myc and E2F1 induce p53 through p14ARF-independent mechanisms in human fibroblasts
A melanoma-predisposing germline CDKN2A mutation with functional significance for both p16 and p14ARF
CANCER LETTERS 2002;180(2):211-21
Role of genetic and epigenetic changes in Burkitt lymphoma
SEMINARS IN CANCER BIOLOGY 2002;12(5):381-7
Inactivation of Myc-induced p53-dependent apoptosis in human tumors
MdmX binding to ARF affects Mdm2 protein stability and p53 transactivation
JOURNAL OF BIOLOGICAL CHEMISTRY 2001;276(27):25336-41
p14ARF homozygous deletion or MDM2 overexpression in Burkitt lymphoma lines carrying wild type p53
Immunolocalization of human p14(ARF) to the granular component of the interphase nucleolus
EXPERIMENTAL CELL RESEARCH 2000;256(2):400-10