We are all familiar with the consequences of loss of tumour-suppressor function, but what about the reverse — is the increased expression of a tumour-suppressor gene a good thing? Manuel Serrano and colleagues have addressed this by generating super transgenic mice that express an additional copy of Ink4a/Arf.

Initially, the authors checked the functionality of the Ink4a/Arf transgene in Ink4a/Arf-null mice and showed that the transgene is regulated like the endogenous gene both during development and in response to oncogenic stress. So, Serrano and colleagues investigated the function of super Ink4a/Arf — where one copy of the transgene is present in addition to the endogenous Ink4a/Arf wild-type loci — in mouse embryo fibroblasts (MEFs) and mice.

The immortalization of cells in culture is commonly associated with loss of either p53 or ARF function, aiding the cells to bypass senescence. After twenty-five rounds of cell passage, 95% of the wild-type MEFs, compared with only 40% of super Ink4a/Arf MEFs, were immortalized. In becoming immortalized, wild-type MEFs showed either loss of p53 or ARF function, whereas the transgenic MEFs lost p53 function only, indicating that the extra copy of Arf was protective. Moreover, super Ink4a/Arf MEFs were more resistant to transformation by either the adenovirus oncogene E1A or oncogenic HRAS-V12.

Are similar results evident in the super Ink4a/Arf mice? Treatment of these animals with a range of carcinogens resulted in reduced tumour formation compared with wild-type littermate controls. Importantly, like Serrano's super p53 mice, the expression of the additional copy of Ink4a/Arf did not affect the ageing process — other transgenic mice overexpressing deregulated p53 have aged prematurely.

Serrano and colleagues conclude that the increased expression of tumour-suppressor genes is protective against tumour formation and that this overexpression is unlikely to be detrimental as long as the gene is regulated and expressed in a manner similar to the endogenous gene. Recent publications have indicated human allelic variability in mRNA expression levels and variable duplicated DNA sequences within the genome, implying that there might be individuals with increased expression of tumour-suppressor genes and a genetically inherited resistance to cancer.