Role of Mxi1 in ageing organ systems and the regulation of normal and neoplastic growth

Nicole Schreiber-Agus, Yong Meng, Tin Hoang, Harry Hou, Ken Chen, Roger Greenberg, Carlos Cordon-Cardo, Han-Woong Lee and Ronald A. DePinho ()
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Nicole Schreiber-Agus: Departments of Molecular Genetics
Yong Meng: Microbiology and Immunology, Albert Einstein College of Medicine
Tin Hoang: Microbiology and Immunology, Albert Einstein College of Medicine
Harry Hou: Microbiology and Immunology, Albert Einstein College of Medicine
Ken Chen: Microbiology and Immunology, Albert Einstein College of Medicine
Roger Greenberg: Microbiology and Immunology, Albert Einstein College of Medicine
Carlos Cordon-Cardo: Memorial Sloan-Kettering Cancer Center
Han-Woong Lee: Microbiology and Immunology, Albert Einstein College of Medicine
Ronald A. DePinho: Microbiology and Immunology, Albert Einstein College of Medicine

Nature, 1998, vol. 393, issue 6684, 483-487

Abstract: Abstract Mxi1 belongs to the Mad (Mxi1) family of proteins, which function as potent antagonists of Myc oncoproteins1,2,3,4. This antagonism relates partly to their ability to compete with Myc for the protein Max and for consensus DNA binding sites and to recruit transcriptional co-repressors4,5,6. Mad(Mxi1) proteins have been suggested to be essential in cellular growth control and/or in the induction and maintenance of the differentiated state6,7. Consistent with these roles, mxi1 may be the tumour-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 adenocarcinoma8,9,10. Here we show that mice lacking Mxi1 exhibit progressive, multisystem abnormalities. These mice also show increased susceptibility to tumorigenesis either following carcinogen treatment or when also deficient in Ink4a. This cancer-prone phenotype may correlate with the enhanced ability of several mxi1-deficient cell types, including prostatic epithelium, to proliferate. Our results show that Mxi1 is involved in the homeostasis of differentiated organ systems, acts as a tumour suppressor in vivo, and engages the Myc network in a functionally relevant manner.

Date: 1998
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DOI: 10.1038/31008

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