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.
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Acknowledgements
We thank A. Skoultchi and members of the DePinho lab for comments; D.Gebhardt, for assistance and advice with FACS studies; L. Chin for graphic-art assistance; C. J. Chang for statistical analysis; and J. Lauridsen for administrative assistance. H.-W.L. and Y.M. were supported by NIH training grants. R.G. was supported by an MSTP training grant. N.S.-A. is a Special Fellow of the Leukemia Society of America. C.C.-C. is supported by grants from the NIH. R.A.D. is supported by grants from the NIH and by the Irma T. Hirschl Award. We acknowledge support from the Albert Einstein Cancer Center Core.
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Schreiber-Agus, N., Meng, Y., Hoang, T. et al. Role of Mxi1 in ageing organ systems and the regulation of normal and neoplastic growth. Nature 393, 483–487 (1998). https://doi.org/10.1038/31008
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DOI: https://doi.org/10.1038/31008
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