Marie Bogoyevitch
Signal transduction in health and disease
The coordination of signal transduction pathways is critical in maintaining normal cellular functions. Our laboratory has a range of interests in signaling events in heart disease, stroke and cancer with the aim of defining signaling events and pinpointing new targets for possible therapeutic intervention.
Projects
All projects will use a range of techniques in cell and molecular biology and biochemistry. Examples of the projects currently offered are outlined below. These are co-supervised by Dr Dominic Ng and Dr Amardeep Dhillon.
1. New regulatory roles for c-Jun N-terminal Kinases (JNKs) in the endoplasmic reticulum stress response
The c-Jun N-terminal kinases (JNKs) are a family of stress-activated protein kinases from the MAPK family that phosphorylate and activate the transcription factor, c-Jun as well as a range of other nuclear and non-nuclear proteins. Important clues on the roles of JNKs have come from JNK gene knockout studies. Specifically, JNKs have been proposed as therapeutic targets in the treatment of a range of diseases including diabetes, atherosclerosis and neurodegeneration. Thus, approaches directed towards inhibiting the activity of JNK have been increasingly explored. In this project, we will interrogate the actions of JNK in the ER stress response. The lead in this area has come from our identification of the interaction between JNK and the pancreatic ER kinase or PKR-like kinase PERK, a known mediator of the ER stress response.
2. Contribution of stathmin-mediated microtubule proliferation to cardiac disease
Microtubules are an essential component of the cell cytoskeleton. In the dividing cell, microtubules are involved in chromosome segregation and organelle (ER, golgi, mitochondria) placement. The function of microtubules in non-dividing, differentiated cardiac muscle cells (myocytes) is less clear. There is evidence that the enhanced proliferation of the microtubule network may contribute to dysfunction of the heart associated with diseases such as cardiac hypertrophy (heart enlargement). However, the proteins that regulate this are unknown. We have demonstrated microtubule hyperproliferation in primary neonatal cardiac myocytes stimulated to hypertrophy. In this project, the contribution of a microtubule-destabilizing protein, stathmin, to enhanced microtubule array proliferation in hypertrophic cardiac myocytes will be evaluated by gene knockdown with siRNAs
3. Differential regulation of Stat3 spliceforms by TC45 phosphatase
The Signal Transducer and Activator of Transcription (STAT) 3 isoform of the family of latent transcription factors is essential for embryonic development and is involved in regulating a wide range of cellular processes. Over-activation of STAT3 is seen in a large number of different cancers. The loss of STAT3 activity in specific cell types also has detrimental effects in the immune system (excessive inflammation), mammary gland development and appetite suppression. STAT3 is activated by JAK-mediated phosphorylation on a critical tyrosine residue (Y705). In contrast, the phosphatase involved in “turning off” STAT3 is unknown. In addition, alternative splicing of the STAT3 gene generates two spliceforms, a full-length a (92 kDa) and a shorter truncated ß (89 kDa) isoform. Currently, differential regulation and functions of the a and ß spliceforms are underappreciated. For example, we have demonstrated that the ß spliceform of STAT3 is preferentially phosphorylated in human heart failure. In this project, the dephosphorylation of STAT3 a and STAT3 ß by the T-cell protein tyrosine phosphatase 45 (TC45) will be evaluated in a STAT3-null background. TC45 mediated interaction and dephosphorylation of exogenously expressed STAT3 a or STAT3 ß will be determined in murine embryonic fibroblasts that lack the STAT3 gene.
4. Relationship between c-Jun and Fra-1 in tumour cells
The Activator Protein-1 (AP-1) transcription factor complex is a central regulator of cell fate decisions and plays a critical role in cancer. Fra-1 is a member of the complex that is expressed at high levels in many epithelial tumours. We have recently found that depleting transformed cells of c-Jun by siRNA leads to the loss of Fra-1 expression but not vice-versa. This project explores the mechanisms underlying how c-Jun could contribute to maintaining the high Fra-1 levels observed in tumour cell lines.
5. Regulation of muscle differentiation by microtubule destabilizing proteins
during development, mono-nucleated immature muscle cells (myoblasts) lose the capacity to divide and fuse into multi-nucleated myotubes. This process of ‘myogenesis’ is central to muscle development. Microtubules are a component of the cell cytoskeleton that is essential for myogenesis. However, the precise function of microtubules is not entirely clear. In addition, the proteins involved in regulating the microtubule array during myogenesis have not been defined. As myoblasts differentiate into myotubes, the expression of the microtubule destabilizing protein, stathmin, is down-regulated to almost undetectable levels. In this project, the potential of stathmin downregulation to induce myoblasts to differentiate in proliferating conditions will be evaluated by RNAi mediated gene knockdown. In addition, the effect of maintaining stathmin expression on myotube formation in differentiating conditions will be investigated.
Lab personnel
HeadAssociate Professor Marie BogoyevitchResearch staffDr Dominic Ng (Doherty Fellow)Ms Yvonne Yeap (Research Assistant) Graduate studentsMariya Misheva Honours studentsBriony Morgan |
Recent publications
- Arthur PG, Matich GP, Pang WW, Yu DY, Bogoyevitch MA. (2007) 'Necrotic death of neurons following an excitotoxic insult is prevented by a peptide inhibitor of c-jun N-terminal kinase.' J Neurochem, 102, 65–76.
- Badrian B, Bogoyevitch MA. (2007) 'Gene expression profiling reveals complex changes following MEK-EE expression in cardiac myocytes'. Int J Biochem Cell Biol, 39, 349–65.
- Badrian B, Casey TM, Lai MC, Rakoczy PE, Arthur PG, Bogoyevitch MA. (2006) 'Contrasting actions of prolonged mitogen-activated protein kinase activation on cell survival'. Biochem Biophys Res Commun, 345, 843–50.
- Bogoyevitch MA, Kobe B. (2006) 'Uses for JNK: the many and varied substrates of the c-Jun N-terminal kinases'. Microbiol Mol Biol Rev, 70, 1061–95. Review.
- Bogoyevitch MA. (2005) 'Therapeutic promise of JNK ATP-noncompetitive inhibitors'. Trends Mol Med, May;11, 232–9.
- Dhillon AS, Hagan S, Rath O, Kolch W. (2007) 'MAP kinase signalling pathways in cancer'. Oncogene, 26, 3279–90.