1. ¹Department of Genetics, Louisiana State University Health Science Center, New Orleans, LA, USA
2. ²Department of Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3. ³Department of Veterinary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
4. ⁴The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA
5. ⁵Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN, USA

Correspondence: Dr T Iwakuma, Department of Genetics, Louisiana State University Health Science Center, New Orleans, LA 70112, USA. E-mail: tiwaku@lsuhsc.edu; Dr G Lozano, Department of Cancer Genetics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. E-mail: gglozano@mdanderson.org

Received 19 June 2007; Revised 21 August 2007; Accepted 1 September 2007; Published online 1 October 2007.

Abstract

Mdm2 inhibits the function of the p53 tumor suppressor. Mdm2 is overexpressed in many tumors with wild-type p53 suggesting an alternate mechanism of loss of p53 activity in tumors. An Mdm2-binding protein (MTBP) was identified using a yeast two-hybrid screen. In tissue culture, MTBP inhibits Mdm2 self-ubiquitination, leading to stabilization of Mdm2 and increased degradation of p53. To address the role of MTBP in the regulation of the p53 pathway in vivo, we deleted the Mtbp gene in mice. Homozygous disruption of Mtbp resulted in early embryonic lethality, which was not rescued by loss of p53. Mtbp^+/- mice were not tumor prone. When mice were sensitized for tumor development by p53 heterozygosity, we found that the Mtbp^+/-p53^+/- mice developed significantly more metastatic tumors (18.2%) as compared to p53^+/- mice (2.6%). Results of in vitro migration and invasion assays support the in vivo findings. Downmodulation of Mtbp in osteosarcoma cells derived from p53^+/- mice resulted in increased invasiveness, and overexpression of Mtbp in Mtbp^+/-p53^+/- osteosarcoma cells inhibited invasiveness. These results suggest that MTBP is a metastasis suppressor. These results advance our understanding of the cellular roles of MTBP and raise the possibility that MTBP is a novel therapeutic target for metastasis.