Our Science – Kalab Website
Petr Kalab, Ph.D.
BiographyInstitute of Animal Physiology and Genetics of the Czech Academy of Sciences in 1990. During his postdoctoral visit at the University of Pennsylvania, Philadelphia, and in his own lab in Czech Republic, he studied signal transduction in mammalian reproduction. In 1997, Dr. Kalab redirected his career and as a visiting fellow at NICHD, NIH, Bethesda, and later as staff researcher at the University of California, Berkeley, focused on the mitotic functions of the small GTPase Ran. In 2008, Dr. Kalab joined the Laboratory of Cellular and Molecular Biology, NCI, NIH as a tenure-track investigator.
My research focuses on two organelles that are characteristic of the internal structure of eukaryotic cells: the nucleus and the mitotic spindle. In particular, it is fascinating that the essential roles of both these organelles require the contribution of a single signaling network controlled by the small GTPase Ran. Because of its fundamental influence, the analysis of Ran-regulated functions provides unparalleled opportunities to study how the nucleus and mitotic spindle are assembled and how they function.
Ran is an evolutionarily conserved key regulator of the nucleo-cytoplasmic transport and has an essential role in the mitotic spindle assembly and in the reformation of the nuclear envelope at the exit from mitosis. The common principle of Ran function is the genome-centered concentration gradient of RanGTP. As Ran GEF (RCC1) binds to DNA and is imported to the nuclei while RanGAP is cytoplasmic, more RanGTP exists around the position of the genome inside the cells, compared to the cell periphery. The functions of the RanGTP gradient are mediated by the interaction of RanGTP with members of the family of nuclear transport receptors (NTRs) of the importin beta superfamily.
Although the role of the Ran-NTR system as a genome positioning system (GPS) is conserved in eukaryotes, its contribution to mitotic spindle assembly differs in comparison of various types of cells (e.g., in meiotic vs. mitotic somatic cells in vertebrates). Importantly, some components of the Ran-NTR system, including Ran and some of the importins, are overexpressed or mislocalized in a variety of human cancers. Many well-known 'cancer proteins' such as BRCA1, HTOG, TACC3, HURP, Aurora A, TPX2, NPM1, survivin, and others are either targets of mitotic Ran regulation or are required for Ran mitotic functions.
Using Forster resonance energy transfer (FRET) biosensors that we developed, we found that, compared to rapidly dividing normal and cancer cells, the mitotic RanGTP gradient was either strongly reduced or non-detectable in normal human somatic cells (Hasegawa et al., J. Cell Biol. 2013, In Press). Moreover, we found that the increased expression of RCC1 and large chromosomal gain (both characteristic to cancer cells) were sufficient to drive the rise of steep mitotic RanGTP gradients. Although many questions remain to be investigated in the future, these results are consistent with the view that the enhanced RanGTP production and steep mitotic RanGTP gradients are adaptive mechanisms supporting the continuous proliferation of certain cancer cells.
Recently, we found evidence suggesting that the activation of many mitosis-promoting genes, including those controlling the formation of steep mitotic RanGTP gradient, is supported by evolutionarily conserved mechanisms directing the spatial chromosome organization in interphase nuclei. The role of such genome-organizing mechanisms has become a new direction of our research (position available - see below).
Postdoctoral or Research Fellow Position is Available
Postdoctoral position is available to investigate the role of genomic organization in mitosis and cell cycle regulation in cancer.
The successful applicant will be expected to join a project examining the role of spatial organization of interphase chromosomes in the control of genes regulating mitosis and cell cycle progression in normal and cancer cells. This project is currently carried in collaboration of three laboratories sharing significant expertise and access to cutting edge technologies within the NIH campus. The main experimental system will be normal and transformed human somatic cells. The experimental approaches will include genomic techniques to interrogate spatial chromosome conformation (4C, DHS), DNA and RNA FISH and variety of cell biological and biochemical analyses.
The qualifications of the applicants should include high motivation, evidence of productivity, willingness and interest to cross boundaries between different fields and at least one of the following:
* A) Ph.D. in molecular and cell biology or biochemistry and a solid background in gene expression regulation, genomic analyses, chromatin structure, epigenetic regulation
* B) Ph.D. in biophysics or physics, strong interest and preferably practical background in cell biology, analytical and computational modeling skills
Interested applicants should send 1) brief statement of research interests 2) CV with bibliography and 3) contacts for 3 references to firstname.lastname@example.org
This page was last updated on 2/20/2013.