MEN1 tumors in humans are restricted to endocrine tissues such as the pituitary, pancreatic islet and parathyroid, although the tumor suppressor menin is ubiquitously expressed. The mechanism of the tissue-specific tumor suppression is yet to be elucidated. Our data indicating the unique requirement for CDK4 suggest that CDK4 activation is essential for a pre-LOH stage of the oncogenic process in the neuroendocrine cell types. While parathyroid tumorigenesis was not examined in the present study, complete inhibition of pituitary and islet tumor development in the Cdk4-null background indicates tight linkage between menin loss and CDK4 activation. Activating mutations of the human CDK4 gene in pituitary, islet or other neuroendocrine tumors have not been reported, whereas activating germline mutations of CDK4 have been described in melanoma-prone families 29-31. These mutations in melanomas affect the Arg24 residue and render the mutant protein resistant to INK4-mediated inhibition. For MEN1 tumorigenesis, downregulation of CDK inhibitors seems to be involved in CDK4 activation. In particular, p18 and p27 have been proposed to play important roles. Menin together with its partner MLL has been shown to control histone methylation at the p18 (CDKN2C) and p27 (CDKN1B) loci for transactivation 32, 33. The levels of p18 and p27 mRNAs in pancreatic islets of Men1+/− mice decline within 28 weeks of age 33. Intriguingly, Cdkn1b−/− mice develop pituitary tumors spontaneously 9, and Cdkn1b−/−; Cdkn2c−/− mice exhibit tumorigenesis with the tissue spectrum overlapping with that of the MEN1 syndrome, including the endocrine pancreas, parathyroid, thyroid, adrenal and pituitary glands 13. A gene expression profiling study, which analyzed pituitary and pancreatic tumors from Men1+/− mice, confirmed p18 downregulation 34. Thus, it is conceivable that downregulation of the CDK inhibitors accounts substantially for ectopic CDK4 activation in pre-oncogenic menin-deficient neuroendocrine cells.