Now researchers working with Prolifix Ltd, a UK drug discovery cell cycle company, have identified a two-stage process by which cells become cancerous in response to oncogenic Ras.

The presence of oncogenic Ras stimulates the production by cells of two antiproliferative tumor suppressor proteins, p19ARF and p53. If either p19ARF or p53 is mutated, the cell escapes growth arrest.

In a paper published in Nature Cell Biology January 18, the researchers reveal that the fail-safe mechanism is dependent on yet another tumor suppressor family, namely, the retinoblastoma proteins.

They show that mutation in two (Rb and p107) or more retinoblastoma family members abolishes p19ARF/p53-dependent protection of cells against the proliferative effects of mutant Ras. Consequently, these cells proliferate indefinitely in the presence of a Ras oncogene.

This suggests that Rb and p107 proteins are essential mediators of the Ras-induced antiproliferative response, which in turn is dependent on p19ARF and p53.

The research also reveals that escape from Ras-induced senescence is not necessarily coupled to acquisition of oncogenic properties. The scientists report that mutation of both the retinoblastoma and p107 tumor suppressor genes allows cells to proliferate indefinitely in the presence of a Ras oncogene but, surprisingly, these cells are unable to induce tumors.

The research was undertaken by Dr. Daniel S Peeper, Dr. Jan-Hermen Dannenberg, Dr. Sirith Douma, Dr. Hein te Riele and Professor Rene Bernards working at the Netherlands Cancer Institute, which has assigned rights to the discovery to Prolifix.

"This research is an important landmark in our understanding of how cells become cancerous," commented Professor Nicholas La Thangue, Prolifix Chief Scientific Officer. "Prolifix is focused on understanding aberrant cell cycle control and how this leads to cancer. We have worked with the Netherlands Cancer Institute for over 7 years and our collaboration continues to yield new targets for therapeutic intervention."

Prolifix, based in Abingdon, Oxfordshire, UK, is a privately owned pharmaceutical company. It is a leader in cell cycle drug discovery and is developing a unique platform technology which enables the company to target pathologically important protein-protein interactions which control the cell cycle.

Prolifix aims to discover and develop novel, small molecule drugs to address diseases associated with aberrant cell cycle regulation. It is focused on cancer and infectious disorders. Several projects are in lead optimization and one has entered pre-clinical evaluation.

24-Jan-2001