Scientists find 'brake-override' proteins that enable development of some cancers

The study, which recently appeared in the early online edition of the Proceedings of the National Academy of Sciences, illuminates the roles of two nearly identical proteins, Cks1 and Cks2. These proteins were known to be overexpressed in many cancers, but scientists hadn't understood why. Now it appears that Cks proteins' overexpression enables cancerous growth by nullifying a natural defense against uncontrolled cell division.

''An initial cancer-promoting gene mutation can push a cell to grow faster, but the cell often detects that something is wrong and sends a signal to its DNA replication machinery to slow down,'' said Steven I. Reed, a professor in the Scripps Research Department of Molecular Biology and senior author of the study. ''We found that when the Cks proteins are overexpressed, they cause incipient cancer cells to ignore that braking signal.''

Speeding Past the Checkpoint

Reed's lab focuses on the basic biology of cell division, and Cks proteins are known to be involved in normal cell division from embryogenesis onwards. Recently, in a routine investigation of the function of Cks proteins in cells, Reed's team used a chemical known as thymidine to temporarily halt the cell division process, to artificially synchronize the growth of two different groups of cells-one with normal Cks expression, and the other with Cks overexpression. To the researchers' surprise, the Cks-overexpressing cells failed to stop dividing.

''That was a serendipitous observation,'' said Reed. ''It led us to hypothesize that these Cks proteins, when overexpressed, are preventing cells from responding to a normal growth-braking signal.''

As a dividing cell unravels its chromosomes, replicates them, and becomes two new cells, it encounters safety ''checkpoints,'' at which the cell division process should stop if the correct signals are not in place. Thymidine inhibits cell division by producing a stop signal at what is known as the ''intra-S-phase checkpoint.'' But somehow, Cks overexpression causes cells to speed past that checkpoint.