Genetics, Molecular Biology, Cell Biology, Developmental Biology
Several organizations (please read below)
10/2013-present Visiting scholar: The regulatory function of nuclear transport in human cancer, Dept. Bioengineering, University of California Berkeley, Berkeley, California
02/2009-08/2013 Principal investigator (four years contract): Genetic manipulations of nuclear transport regulators and aberrant cell signaling in Drosophila, Genetics division, Dept. Cell & Molecular Biology, University of Gothenburg, Gothenburg, Sweden
12/2004-02/2009 Project leader: Molecular analysis of CRM1-mediated protein export in Drosophila, Dept. Developmental Biology, Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
10/2002-12/2004 Post doctoral associate: Regulation of nucleocytoplasmic transport in Drosophila melanogaster, Dept. Developmental Biology, Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
10/1997-07/2002 Graduate student: Molecular and structural analysis of nucleoplasmic proteins connected to post-transcriptional steps of gene expression in dipteran Chironumus tentants, Dept. Cell & Molecular Biology (CMB), Karolinska Institute and Dept. Molecular Biology & Functional Genomics, Stockholm University, Stockholm, Sweden
11/1995-10/1997 Research assistance: Regulation of radio-sensitivity in human prostate cancer cells, National Institute for Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
08/1993- 11/1995 Masters student: Study of chromosomes and soluble proteins in four species of Vinca growing in Iran, Dept. Physiology, University of Tehran, Tehran, Iran
2009-2013 Lecturer, Genetics division, Dept. Cell & Molecular Biology, University of Gothenburg, Gothenburg, Sweden
Courses: Developmental Biology, Molecular Biology, The cell: A molecular approach, and Molecular Biology methods
2009-2013 Supervisor, Genetics division, Dept. of Cell & Molecular Biology, University of Gothenburg, Gothenburg, Sweden
B.Sc. students: Nerges Winblad Niklas Andersson
M.Sc. students: Sansan Hua, Manoj Sonav
The Regulatory Function of Nuclear Transport in Drosophila
Eukaryotic chromosomes are resided in the nucleus, the structure that is delimited by the double membranes of the nuclear envelope (NE). This physical barrier provides eukaryotic cells with a critical control mechanism separating the site of gene transcription from the site of protein synthesis. This compartmentalization endows cells to efficiently coordinate many key cellular processes, but it also presents cells with the challenge of selectively regulating the transport of a very large number of RNAs and proteins. In higher eukaryotes, major pathological processes are associated with altered nuclear transport, and many viruses target components of the nucleocytoplasmic transport machinery to hijack it (Faustino et al. 2007; Chahine and Pierce 2009). Recent studies have revealed the enormous potential for how we might be able to specifically control different cellular processes by interventions targeting the transport factors and the nuclear pore complex (NPC, a large protein assembly embedded in the NE which, in conjunction with transport factors, govern all macromolecular exchange between the nucleus and cytoplasm). Yet, much remains to be discovered to understand the molecular mechanisms underlying nuclear transport in sufficient detail to design interventions and to estimate their effects.
My work as a postdoctoral associate and project leader at Christos Samakovlis’ lab revealed a unique requirement for the two NPC proteins Nup88 and Nup214 in the activation of innate immunity responses (Roth et al., J. Cell Bio. 2003; Xylourgidis et al., J. Cell Sci. 2006). Through this, my colleagues and I showed, for the first time, that the NPC itself has a high regulatory potential and that the nuclear pore proteins might be very valuable candidates for future gene manipulation and drug therapy. During my postdoc, I also discovered that the nuclear protein RanBP3 is essential for the function of CRM1, one of the major export factors in all eukaryotic cells from yeast to human. I further showed that RanBP3 and Nup214 antagonize each other to fine tune the level of CRM1 inside the nucleus (Sabri et al., J. Cell Bio. 2007). Nuclear concentration of CRM1 is the ”core” determinant in the export of tumor suppressors (ex. Retinoblastoma, APC, p53, FOXO, RASSF2 and BRCA1), cell cycle inhibitors (ex. p21CIP1, p27KIP1 and Tob), apoptosis factors (ex. Galectin-3 and Bok), the oncogene BCR-ABL, the cytoskeleton regulator N-WASP/FAK, the chaperon Hsp90, and many other proteins implicated in human cancers (Turner et al., 2012).
While the necessity of specific NPC components in the assembly of metazoans NE had been reported by several studies, the underlying mechanisms behind it were left unexplored due to the ”essential” function of the candidate proteins in cell growth and survival. To overcome this problem, I sought to take advantage of the hypomorphic situation of RNA interference systems. So under my supervision as a principal investigator and through a strong funding support from multiple Swedish foundations, my research group used a combination of RNA interference rescue assays, protein binding tools and microscopic analysis to study the NPC protein Nup155. We discovered that the different regions of Nup155 play distinct roles: The N-terminal of Nup155 is required for the anchoring of the protein to the NPC, while the middle part of Nup155 is necessary for the targeting of nuclear membrane proteins to the NE. This finding was particularly interesting because it showed, for the first time, that a pore component could have independent functions in nuclear membrane biogenesis and NPC structure. Our study also provided a time frame for the segregation of nuclear membrane proteins from the endoplasmic reticulum (Busayavalasa et al., J. Cell Sci. 2012). A mutation in human Nup155 results in atrial fibrillation, the most common heart rhythm disturbance, affecting over 2,000,000 people in the united states (Zhang et al., 2008; Lloyd-Jones et al., 2010). Whether this cardiac disorder is originated from Nup155-related NPC or NE deficiencies remains unknown.
Hedgehog (Hh), as an example, is one of the pathways that is altered in many cancers (Taipale and Beachy, 2004). Not surprisingly, therapeutic approaches to control Hh activity are subject of an intense and rapidly expanding research field. Several Hh inhibitors, mainly ones targeting upstream components of the pathway, have already been developed. Similar to other targeted therapies, however, the best strategy would be targeting something downstream. I am very passionate about understanding the molecular mechanisms of novel regulators, which affect downstream components of Hh and other cell signaling pathways. I believe these proteins have enormous potential to offer safer and more efficient ways to manipulate signaling activity in cancer patients. In this regard, a broad range of techniques such as live microscopy, immunopurification approaches, transcriptional reporters and tumorigenicity assays propel us toward our research goals. Our main research tool is the fruit fly Drosophila melanogaster. Jerry Yin, a Professor of Genetics at the University of Wisconsin-Madison says: “mammals are too complex, most of the time, to ‘see’ the simpler underlying logic. The basic ‘biological logic’ for almost all problems is first worked out in simpler organisms, then the answers are ‘searched for’ in mammals” (Hunter, 2008). My current focus is to understand how nuclear transport is involved in the abnormal activity of transcription factors (i.e., one of the most downstream effectors) in cell signaling pathways.