ROLE OF MXI1 IN AGING ORGAN SYSTEMS AND THE REGULATION OF NORMAL AND NEOPLASTIC GROWTH

Mxi1 belongs to the Mad (Mxi1) family of proteins, which function as p otent antagonists of Myc oncoproteins(1-4). This antagonism relates pa rtly to their ability to compete with Myc for the protein Max and for consensus DNA binding sites and to recruit transcriptional co-represso rs(4-6). Mad(Mxi1) proteins have been suggested to be essential in cel lular growth control and/or in the induction and maintenance of the di fferentiated state(6-7) Consistent with these roles, mxi1 may be the t umour-suppressor gene that resides at region 24-26 of the long arm of chromosome 10. This region is a cancer hotspot, and mutations here may be involved in several cancers, including prostate adenocarcinoma(8-1 0). Here we show that mice lacking Mxi1 exhibit progressive, multisyst em abnormalities. These mice also show increased susceptibility to tum origenesis either following carcinogen treatment or when also deficien t in Ink4a. This cancer-prone phenotype may correlate with the enhance d ability of several mxi1-deficient cell types, including prostatic ep ithelium, to proliferate. Our results show that Mxi1 is involved in th e homeostasis of differentiated organ systems, acts as a tumour suppre ssor in vivo and engages the Myc network in functionally relevant mann er.