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Carcinogenesis Advance Access published online on September 24, 2007
Carcinogenesis, doi:10.1093/carcin/bgm207
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Cell lineage-specific interactions between Men1 and Rb in neuroendocrine neoplasia

Andres Matoso1, Zongxiang Zhou1, Ryo Hayama, Andrea Flesken-Nikitin and Alexander Yu. Nikitin

Department of Biomedical Sciences, Cornell University, Ithaca, NY

Correspondence: Alexander Yu. Nikitin, Department of Biomedical Sciences, Cornell University, T2 014 VRT Campus Road, Ithaca, NY 14853. E-mail: an58{at}cornell.edu

Inactivation of Multiple Endocrine Neoplasia (MEN) type 1 gene (Men1) results in development of multiple endocrine tumors in Men1 mice and in humans. Intriguingly, loss of the wild-type retinoblastoma 1 (Rb) gene also leads to MEN-like phenotype in Rb mice. To evaluate potential genetic interactions between these genes, we prepared and characterized Men1Rb compound mice in parallel with their parental genotypes. Men1 and Rb did not cooperate in tumor suppression, as demonstrated by comparable survival rates of Rb and Men1Rb mice, absence of tumor growth acceleration and lack of novel neoplasms. Notably, the loss of the remaining copy of the wild-type Men1 and Rb was mutually exclusive in all tumors of Men1Rb mice, including pituitary anterior lobe and adrenal medulla neoplasms shared by Rb- and Men1-deficient phenotypes. Downregulation of Men1 targets p18 and p27 and increased presence of phosphorylated-Rb were observed in Men1-deficient pheochromocytomas of Men1 Rb and Men1 mice. At the same time, the RNAi knock-down of Men1 mRNA resulted in increased apoptosis of Rb-deficient medullary thyroid carcinoma cells. These results demonstrate that, depending on cell lineage context, combined Men1 and Rb deficiency may be either redundant or detrimental to neoplastic growth. Identification of cell lineage-specific interactions between Men1 and Rb may have important implications for development of rationally designed therapeutic approaches.

Key Words: genetically modified mice • menin • multiple endocrine neoplasia • retinoblastoma

1 These authors contributed equally to this work.

Received May 18, 2007; revised September 5, 2007; accepted September 12, 2007.


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