UCL Cancer Institute

Cancer cell signalling - proliferation and fate control



Group Leader: Professor Sibylle Mittnacht



Research Summary

Professor Sibylle Mittnacht

A question with fundamental relevance to cancer biology is what determines whether cells (which form the building blocks of tissue including cancer) divide or cease to divide.

The stringent control of cell division is a prerequisite for the precise formation of organs and body organization during embryonic development as well as tissue renewal and tissue maintenance thereafter. In normal tissue cell division is confined to a small group of tissue cells that in an externally controlled manner produce progeny that have limited division capacity and finally enter a state of terminal division incapacity or die. A defect in this control is elementary to the development of cancer and found in cancer cells of all cancer types. Because of such defects cancer cells enter division independent of external control and remain proliferation active under conditions where normal cells are unable, or cease, to divide. Loss of division control is critically important for the ability of cancers to expand at their primary site as well as for the ability of cancer metastasis to establish following spreading of individual cancer cells to remote tissues.

We are trying to understand the molecular machinery required for cells to enter the cell division cycle and the mechanisms that leads cells to cease division activity transiently and terminally. Our efforts include investigating if and how such understanding may be exploited for the therapy and cure of cancer and how the molecular machinery impacts therapeutic outcome following conventional and targeted cancer therapeutic intervention. Our research uses a combination of molecular, cell and biochemical technologies, including cell-based high contend screens using chemicals and RNA interference-mediated gene- knock- down, molecular engineering, proteomics and enzyme activity assays.


Research Projects

The decision whether to enter cell division arises in the GAP1 (G1) phase of the cell cycle and normally required stimuli from the external environment. Once the decision is made the cell progress through the division cycle generating two daughter cells. At the centre of the decision making mechanisms acts the retinoblastoma tumour suppressor protein and its relatives. The retinoblastoma protein holds cell cycle progression and promotes terminal cell cycle exit unless it becomes phosphorylated at the hands off protein kinases of the cyclin dependent kinase family. A myriad of signalling events converge to hold and fold this phosphorylation thereby providing a crucial decision making process in proliferation control. Projects of the group aim at understanding how G1 checkpoint transit is controlled and characterize the molecular consequence to checkpoint activation.


Understanding what is required for cells to pass the G1 checkpoint

Professor Sibylle Mittnacht

We are using high contend cell-based assays in combination with RNA interference to map signalling networks that are required for the inactivation of the retinoblastoma tumour suppressor protein controlled G1 checkpoint.

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Understanding what makes cells stop- Signalling requirement for stress-mediated G1 checkpoint activation

Professor Sibylle Mittnacht

The work seeks to map signalling required for the inactivation of G1 checkpoint by environmental and cancer therapeutic stress.

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Determining modifiers of cdk inhibitor sensitivity

Professor Sibylle Mittnacht

The project uses high contend screening to identify modifiers of G1 checkpoint activation by CDK targeting therapeutic agents.
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Proof-of-concept oncology target validation for retinoblastoma protein activation screen (Rb screen) hits.

The project seeks validation around selected targets required for G1 checkpoint inactivation to justify initiation of a discovery programme for small molecule agents for the inhibition of cancer cell proliferation.



Proteomics based analysis of the RB N domain function

Professor Sibylle Mittnacht

We are seeking to identify a function of the Retinoblastoma protein N terminal domain using mass spec based binding protein identification.
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Biography


Sibylle Mittnacht is Professor of Molecular Cancer Biology and a fellow of the Royal Society of Medicine (RSM). Professor Mittnacht received a BSc/MPhil from the Eberhard Karl’s University, Tubingen, Germany in 1983 and a PhD from the German Cancer Research Centre, University of Heidelberg in 1987, with subsequent postdoctoral training in the Department for Applied Tumour Virology at the German Cancer Research Centre (1987-88) and the Weinberg Laboratory at the Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge MA, USA (1988-1992). In 1993 she joined the Institute of Cancer Research (ICR) London as career development faculty, with promotion to career faculty in 1998. Dr Mittnacht received awards including the Yamagiwa-Yoshida Memorial International Cancer Study Award, International Union Against Cancer (UICC), Geneva, Switzerland (1985), an award by the German Cancer Research Foundation in support of novel approaches to cancer research, a career award by the German Cancer Research Foundation in support of highly gifted young scientists (1987- 1989) and a postgraduate award of the Boehringer Ingelheim Fonds, Germany (1989-1991). In 2011 Professor Mittnacht joined the UCL Cancer Institute as a group leader and honorary faculty. Her main interests are the regulation and the mechanism of G1 proliferation checkpoint control.

Links

BiomedExperts       Cancer Research UK


 

Selected references

Barrie SE, Eno-Amooquaye E, Hardcastle A, Platt G, Richards J, Bedford D, Workman P, Aherne W, Mittnacht S, Garrett MD. High-throughput screening for the identification of small-molecule inhibitors of retinoblastoma protein phosphorylation in cells. Anal Biochem. 320(1):66-74. 2003. Pubmed

Krutzfeldt, M., Ellis, M., Weekes, D.B., Bull, J.J., Eilers, M., Vivanco, M.D., Sellers, W.R. and Mittnacht, S. Selective Ablation of Retinoblastoma Protein Function by the RET Finger Protein. Mol Cell. 18, 213-24. 2005. Pubmed

Sánchez-Sánchez F, Ramírez-Castillejo C, Weekes DB, Beneyto M, Félix Prieto F, Nájera C., Mittnacht S. Attenuation of disease phenotype through alternative translation initiation in low penetrance retinoblastoma. Hum Mutat. 28(2): 159-167. 2007. Pubmed

Hassler, M., Singh, S., Yue, W.W., Luczynski, M., Lakbir, R., Sanchez-Sanchez, F., Bader, T., Pearl, L.H., and Mittnacht, S. Crystal structure of the retinoblastoma protein N domain provides insight into tumor suppression, ligand interaction, and holoprotein architecture. Mol Cell 28, 371-385. 2007. Pubmed

Cuomo, M.E., Knebel, A., Morrice, N., Paterson, H., Cohen, P., and Mittnacht, S. (2008). p53-Driven apoptosis limits centrosome amplification and genomic instability downstream of NPM1 phosphorylation. Nat Cell Biol 10, 723-730. 2008. Pubmed

All publications by Sibylle Mittnacht

 


 

Group Leader

Professor Sibylle Mittnacht, Group Leader

Tel: (44) 020 7679 6500
sibyllemittnacht@gmail.com

Group Members

  • Postdoctoral scientist – TBA
  • Postdoctoral scientist – TBA
  • Postdoctoral scientist – TBA
  • PhD student – Rebecca Cook
  • PhD student – Chi Zhang (in collaboration with the Section of Cancer Therapeutics, Institute of Cancer Research)

 




 

Collaborators

  • Dr. Paul Huang, The Institute of Cancer Research, London
  • Professor Laurence Pearl, Sussex University
  • Professor Dietmar Lohmann, Essen, Germany
  • Professor Paul Workmann The Institute of Cancer Research, London

 




 

Funders