Research units - Cell Cycle and Cancer

Cell Cycle and Cancer

In higher eukaryotes, controlled cell proliferation and differentiation is required for normal growth and development. Deregulation of cell growth pathways leading to unrestrained cell division is a primary characteristic of cancerous cells. Therefore, defining the causes of increased cellular division is fundamental to understanding the development of human cancer.

Research Overview

Controlled cell proliferation and differentiation is required for normal growth and development. Deregulation of cell growth pathways leading to unrestrained cell division is a primary characteristic of cancerous cells. Therefore, defining the causes of increased cellular division is fundamental to understanding the development of human cancer. Two fundamental biochemical processes which control cell division are protein phosphorylation, mediated by the cyclin-dependent kinases (CDKs), and protein degradation mediated by the ubiquitin-dependent proteolytic pathway. Deregulated CDK activity is intimately involved in the development of many human cancers due to increased cell division. Therefore, an important unresolved issue relates to understanding and defining the molecules targeted by CDKs, which mediate the adverse effects of deregulated CDK activity.

To address these issues, we have developed novel methods to systematically identify targets of CDKs, and numerous targets have been discovered. Current research involves characterising these newly identified CDK targets. In addition, a major focus relates to understanding how ubiquitin-conjugating enzymes and ubiquitin ligases control proteolysis and cell division. These enzymes are critical for cell division and their deregulated activity can promote carcinogenesis. These studies will lead to an increased understanding of the molecular mechanisms of cell division providing insight into the development of human cancer.

Research Themes

Regulation of G1-S phase cell cycle progression

Regulation of proliferation and metastasis by cyclin/CDK-mediated phosphorylation of the RBP1 tumour

Regulation of cell cycle control by the ubiqutin-conjugating and ubiquitin ligase enzymes

Honours and PhD Projects

Regulation of growth factor signaling and cell cycle progression

Regulation of proliferation and metastasis in breast cancer

Regulation of cell cycle progression in human cancer

Staff

Staff image

Dr Boris Sarcevic
Dr Randy Suryadinata

Publication Highlights

  1. Randy Suryadinata, Martin Sadowski, Rohan Steel and Boris Sarcevic (2011) Cyclin-dependent kinase-mediated phosphorylation of RBP1 and pRb promotes their dissociation to mediate release of the SAP30/mSIN3/HDAC transcriptional repressor complex  J. Biol. Chem. 286, 5108-5118
  2. Martin Sadowski, Randy Suryadinata, Xainning Lai, Jorg Heierhorst and Boris Sarcevic (2010) Molecular basis for lysine specificity in the yeast ubiquitin-conjugating enzyme Cdc34 Mol. Cell. Biol. 30, 2316-2329
  3. Martin Sadowski, Rohan Baker, Amanda Mawson and Boris Sarcevic (2007) Cdc34 C-terminal tail phosphorylation regulates Skp1/cullin/F-box (SCF)-mediated ubiquitination and cell cycle progression Biochem. J. 405, 569-581
  4. Amanda Mawson, Angela Lai, Jason S. Carroll, C. Marcelo Sergio, Christopher J. Mitchell and Boris Sarcevic (2005) Estrogen and insulin/IGF-1 cooperatively  stimulate cell cycle progression in MCF-7 breast cancer cells through differential regulation of c-Myc and cyclin D1 Molec. Cell. Endocrinol 229, 161-173
  5. Megan Fabbro, Bin-Bing Zhou, Mikiko Takahashi, Boris Sarcevic, Preeti Lal, Mark E. Graham, Brian G. Gabrielli, Phillip J. Robinson, Erich A. Nigg, Yoshitaka Ono and Kum Kum Khanna  (2005) Cdk1/Erk2- and Plk1-dependent phosphorylation of a centrosome protein, Cep55, is required for its recruitment to midbody and cytokinesis Dev. Cell 9, 477-488
  6. Timothy C.Tan, Valentina A. Valova, Chandsra S. Malladi, Mark E. Graham, Leise A. Berven, Orla J. Jupp, Gurdip Hansra, Sonya J. McClure, Boris Sarcevic, Ross A. Boadle, Martin R. Larsen, Michael A.Cousin and Phillip J. Robinson  (2003)  Cdk5 is essential for synaptic vesicle endocytosis Nat. Cell Biol. 5, 701-710
  7. Boris Sarcevic, Amanda Mawson, Rohan T. Baker and Robert L. Sutherland (2002) Regulation of the ubiquitin-conjugating enzyme hHR6A by CDK-mediated phosphorylation  EMBO J.  21, 2009-2018
  8. Boris Sarcevic, Richard Lilischkis and Robert L. Sutherland (1997) Differential Phosphorylation of T-47D Human Breast Cancer Cell Substrates by D1-, D3-, E- and A-, Cyclin/CDK Complexes. J. Biol. Chem. 272, 33327-33337           
  9. Boris Sarcevic, Eleanor Erikson and James L. Maller. (1993)  Purification and Characterisation of a Mitogen-activated Protein Kinase Tyrosine Phosphatase from Xenopus Eggs.  J. Biol. Chem. 268, 25075-25083
  10. Olivier Haccard, Boris Sarcevic, Andrea Lewellyn, Rebecca Hartley, Linda Roy, Tetsuro Izumi, Eleanor Erikson and James L. Maller. (1993) Induction of Metaphase Arrest in Cleaving Xenopus Embryos by MAP Kinase.  Science 262, 1262-1265