The main focus of Prof. Jans' work has been to delineate the mechanisms regulating protein transport to the nucleus, which is central to many important cellular processes such as differentiation, transformation, signal transduction and the regulation of transcription. His signature approach has been to use biophysical approaches (eg. quantitative confocal laser scanning microscopy - CLSM/image analysis) together with microinjection or reconstituted in vitro systems to examine nuclear protein import kinetics at the single cell level, as well as various binding approaches utilizing fluorescent measurements (eg. fluorescence polarization/ fluorography/ALPHAscreen) to analyse the initial step of nuclear transport - that of targeting signal (nuclear localization sequence - NLS) recognition by members of the cellular importin (IMP) nuclear import receptor/transport. He also pioneered the use of the technique of fluorescence recovery after photobleaching (FRAP) to determine nuclear transport kinetics in living cells.
Using these predominantly quantitative approaches, the Jans lab. has made a number of major contributions to knowledge of nuclear transport, especially with respect to its regulation (see below). For example, his lab. showed that whilst nuclear localisation is NLS-dependent, phosphorylation at sites near NLSs can either enhance or inhibit NLS-dependent nuclear transport; hormonal signals can modulate gene expression through regulating phosphorylation at such sites, thereby specifically controlling the nuclear entry of particular TFs. His lab. defined for the first time the mechanism by which NLS-dependent nuclear protein transport can be enhanced by phosphorylation; through phosphorylation enhancing IMP-NLS interaction in the case of the Drosophila morphogen Dorsal and simian virus SV40 large tumour-antigen (T-ag). His lab. has worked intensively on the nuclear import pathways used by viral proteins, and in particular those of the HIV-1 and Dengue viruses, the causative agents of AIDS and Dengue fever, respectively, as well as Rabies virus, and viruses causing respiratory disease/asthma exacerbation such as respiratory syncytial virus and rhinovirus. The strategy has been to define the import pathways of these proteins and the regulation thereof, and thereby identify potential targets for the future development of anti-virals to block viral infection. The lab. has also used knowledge of nuclear protein import in order to target molecules of interest to the nucleus in a research or clinical setting. This has included the nuclear delivery of DNA of relevance to gene therapy applications (eg. the introduction of normal gene copies into appropriate cells harbouring a genetically conferred error of metabolism), or alternatively, of toxins to the nucleus of tumour cells with relevance to anti-cancer therapy applications. The approach here has been to use modular conjugate molecules containing modified NLSs with these applications in mind, the more recent interest work being a tumour cell specific nuclear targeting signal from chicken anaemia virus (CAV) VP3 protein, which intriguingly shows phosphorylation-regulated nuclear localization in tumour cells, but not normal cells.
Professor Jans' General Profile
Professor Jans' publications
