The Functioning of Rb
Rb is found in the nucleus of virtually every cell in the body. Its function relies on promoting the formation of multi-component complexes that involve cellular transcription factors required for cell replication and the promotion of differentiation. As a consequence, Rb prevents cell division and promotes cell differentiation and senescence.
Rb binds to its cellular ligands only when un- or poorly phosphorylated and this form hence is considered the active species of the tumour suppressor. Rb's phosphorylation state is managed through complex signalling networks sensing intra- and extracellular cues. These cues are relayed to permit or hold Rb phosphorylation. Loss of Rb protein function or its control is deemed to result in inappropriate cell proliferation and loss of ability to differentiate and/or senesce - these providing important stepping stones for cancer development.
Phosphorylation of the Retinoblastoma Tumour Suppressor Protein and Cellular Growth Control
S Mittnacht, G Platt, S Stockwell, M Hassler, JJ Bull, D Weekes; in collaboration with the Cancer Research UK Centre for Cancer Therapeutics and the Section of Structural Biology
Source of external funding: Cancer Research UK, MRC
Activation of the tumour suppressor retinoblastoma protein (Rb) involves its conversion into a nonphosphorylated form. In collaboration with the Cancer Research UK Centre for Cancer Therapeutics we have identified several drug-like molecules that promote the accumulation of nonphosphorylated, active Rb in cells. These molecules inhibited the multiplication of cells in culture with great efficacy, in keeping with the hypothesis that the active form of Rb blocks the generation of cell progeny. They thus may constitute novel prototype agents for facilitating a block of cancer cell proliferation in patients.
One consequence of Rb activation in cells is the induction of cell aging, which is associated with differentiation activity and terminal inability to produce progeny. Through structure function analysis of Rb and its subdomains we are seeking to understand how Rb elicits these effects.
Our work also is beginning to provide evidence that these consequences arise only in actively dividing cells and further that molecules exist which selectively interfere with at least one of these Rb responses. Thus, therapeutic intervention that leads to Rb activation may not provoke differentiation and aging in normal, non-dividing body cells but may selectively do so in tumour cells where division control is lost. These results also infer that Rb activating therapeutics may prove most powerful in highly active and aggressive tumours.
In the Section of Cell and Molecular Biology (including the Cancer Research UK Centre for Cell and Molecular Biology)
