Divecha, Nullin - University of Southampton - Discipline of Biological Sciences

个人简介

Career History 2015-2017: joint position European fellow, Institute of molecular genetics (INGM), Milan, Italy. 2014 - Present: Associate Professor, Biological Sciences, University of Southampton 2007-2013: Senior PI The Manchester Cancer Institute, Manchester Uk 1997-2007: Senior PI, The Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands. 1993-1997: Junior Group leader, the Babraham Institute, Cambridge, UK 1988-2003: Postdoctoral fellow, Prof. R. F. Irvine, the Babraham Institute, Cambridge, UK 1985-1988: Post graduate, Dr. Charles McDonald, Biochemistry, Sheffield University, Sheffield, UK 1982-1985: Undergraduate, Biochemistry, University of Manchester, Manchester, UK. Academic Qualification 1985-1988: Ph.D: the role of proline Rich Proteins; University of Sheffield, UK 1982-1985: BSc; Biochemistry, University of Manchester, UK

研究领域

Cancer, inflammation, diabetes and many other diseases can be considered to be the result of deregulated signalling pathways that normally enable the cell to properly respond to environmental changes. Phosphoinositides are a family of seven lipid messengers that are present in many subcellullar compartments (figure 1 ). Specific subcellullar phosphoinositide profiles are controlled by kinases, phosphatases and phospholipases which respond to both extracellular and intracellular cues. In this manner phosphoinositides transduce environmental stimuli into downstream cellular responses. Amongst other mechanisms phosphoinositides transduce signals by interacting with proteins to change the proteins intracellular location or function (figure 2). We are particularly interested in phosphoinositides in the nucleus. While it is still not clear how phosphoinositides are presented in the nucleus nor how they are controlled we and others have shown that their levels are changed in response to many different types of stimuli and that they are able to interact with and regulate proteins that are involved in nuclear functions such as transcription, mRNA processing and export and DNA conformation. One specific protein domain that appears to act as a nuclear receptor for phosphoinositides is called the PHD finger, which is a zinc finger that is present in proteins that are predominantly nuclear and that are involved in epigenetic signalling. Epigenetic signalling is essentially a mechanism by which environmental stimuli can impact on both short and long term gene transcriptional otput and thereby control cell fate decisions. DNA is wrapped up into nucleosomes by its interaction with histone proteins which then form higher order structures called chromatin. Chromatin forms at least seven different molecular structures which are differently associated with trasncriptional output. In essence epigenetic signaling involves the reversible enzymatic modification of DNA and of the histone proteins which appears to modify chromatin structure. Many of the proteins involved in placing (writers), removing (erasers) and interpreting (readers) these modifications can interact with and be regulated by nuclear phosphoinositides. For example TAF3 is a component of the multisubunit basal transcription complex that has a PHD finger that interacts with phosphoinositides. We showed recently that its interaction with phosphoinositides changes its ability to regulate muscle specific gene transcription and thereby muscle cell differentiation (figure 3). In this study we also showed that many other PHD finger containing proteins interact with phosphoinositides (DOI: http://dx.doi.org/10.1016/j.molcel.2015.03.009) Our goal is to understand exactly how nuclear phosphoinositides are regualted, how they impact on nucelar functions and how they are deregulated in diseases. As the enzymes that modulate nuclear phosphoinositides are inherently druggable we believe that they will provide novel molecular targets with which to combat various diseases. Figure 1: the profile of phosphoinositides defines identity and fuction of subcellular compartments. Different phosphoinositides appear to confer identity to subcellular compartments. By interacting and regualting specific proteins these phosphoinositides also confer subcellular specific functions (see figure 2) Figure 2. phosphoinositides control cellular processes by interacting with specific proteins. Different phsophoinositides can interact with proteins through specific domains. For example PtdIns3P interact strongly with FYVE domain containing proteins, while PtdIns(4,5)P2 interacts with a sub-family of PH domain containing proteins. The interaction induces phosphoinositide specific control of downstream processes. Figure 3. TAF3 is a PHD finger containing proteins that confers phosphoinositidide sensitivity to the basal transduction complex. The PHD finger of TAF3 interacts with nuclear PtdIns5P to regulate muscle specific gene transcription and thereby control muscel cell differentiation.

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PIP4K and the role of nuclear phosphoinositides in tumour suppression - Fiume, Roberta, Stijf-Bultsma, Yvette, Shah, Zahid H, Keune, Willem Jan, Jones, David R., Jude, Julian Georg and Divecha, Nullin Published:2015Publication:Biochimica et Biophysica ActaVolume:1851, (6)Page Range:898-910doi:10.1016/j.bbalip.2015.02.014PMID:25728392 The basal transcription complex component TAF3 transduces changes in nuclear phosphoinositides into transcriptional output - Stijf-Bultsma, Yvette, Sommer, Lilly, Tauber, Maria, Baalbaki, Mai, Giardoglou, Panagiota, Jones, David R., Gelato, Kathy A., van Pelt, Jason, Shah, Zahid, Rahnamoun, Homa, Toma, Clara, Anderson, Karen E., Hawkins, Philip, Lauberth, Shannon M., Haramis, Anna-Pavlina G., Hart, Daniel, Fischle, Wolfgang and Divecha, Nullin Published:2015Publication:Molecular CellVolume:58, (3)Page Range:453-67doi:10.1016/j.molcel.2015.03.009PMID:25866244 The basal transcription complex component TAF3 transduces changes in nuclear phosphoinositides into transcriptional output - Stijf-Bultsma, Yvette, Sommer, Lilly, Tauber, Maria, Baalbaki, Mai, Giardoglou, Panagiota, Jones, David R., Gelato, Kathy A., van Pelt, Jason, Shah, Zahid, Rahnamoun, Homa, Toma, Clara, Anderson, Karen E., Hawkins, Philip, Lauberth, Shannon M., Haramis, Anna-Pavlina G., Hart, Daniel, Fischle, Wolfgang and Divecha, Nullin Published:2015Publication:Molecular Celldoi:10.1016/j.molcel.2015.03.009 A targeted knockdown screen of genes coding for phosphoinositide modulators identifies PIP4K2A as required for acute myeloid leukemia cell proliferation and survival - Jude, J.G., Spencer, G.J., Huang, X., Somerville, T.D.D., Jones, D.R., Divecha, N. and Somervaille, T.C.P. Published:2015Publication:OncogeneVolume:34, (10)Page Range:1253-1262doi:10.1038/onc.2014.77PMID:16642045