The requirement for CDK4 in tumorigenesis of Men1+/− mice expands upon its physiologic role previously demonstrated in the pituitary and pancreatic islets in Cdk4−/− mice 14, 15. It is important that this phenotype is restricted to adult mice, while embryonic development of these organs is completely intact 18-20. Regarding murine pancreatic islets, it is possible that CDK4 activity is essential for proliferation of differentiated β cells, which is thought to be a major mechanism for the adaptive regulation of islet mass in response to homeostatic requirement for insulin secretion 35. A similar scenario might apply to the regulation of adult pituicyte proliferation. A recent study proposed that downregulation of menin promotes β cell proliferation during pregnancy 36. Thus, menin could be a limiting factor for not only tumorigenesis but also physiological proliferation in adult endocrine tissues, presumably via CDK4 inhibition. Pancreatic islets and pituitaries in Cdkn2c−/−; Cdk4−/− double mutant mice are as hypoplastic as Cdk4−/− mice 37, indicating a linear functional relationship between p18 and CDK4. While CDK6 is another target of p18 and this kinase has also been implicated in the control of human islet proliferation 38, genetic evidence suggests that murine islet cells depend solely on CDK4 for proliferation and tumorigenesis. Moreover, CDK4 expression was robust in islet tumors of Men1+/− mice, suggesting that upregulation of CDK4 protein may cooperate with downregulation of the CDK inhibitors in Men1+/− neuroendocrine cells. This notion is consistent with a recent report that a number of human pancreatic neuroendocrine tumors expressed high levels of CDK4 39. We hypothesize that CDK4 activation not only accelerates proliferation but also generates a selective pressure for cells with LOH at the Men1 locus. To further delineate the role of CDK4 in pituitary tumorigenesis triggered by the loss of menin, we recently generated mice with pituitary-specific disruption of MEN1, using Cre transgenic mice under the growth hormone promoter (rGHp-Cretg+) crossed with mice with a floxed Men1 allele (Men1lox/lox). While rGHp-Cretg+; Men1 lox/lox; Cdk4+/+ mice displayed large pituitary tumors by 7 months of age with complete penetrance, no tumor was detected in rGHp-Cretg+; Men lox/lox; Cdk4−/− mice autopsied at 9 months (Gillam et al., unpublished observations). Since the GH promoter becomes active during late embryogenesis, homozygous loss of menin in this model occurs earlier than any detectable impact of Cdk4 deficiency on pituitary proliferation or differentiation. Thus, the abrogation of tumorigenesis observed in Men1+/−; Cdk4−/− mice results from the requirement for CDK4 in neuroendocrine tumor initiation, and is unlikely to reflect other functional defects in hypoplastic pituitary or islets in Cdk4−/− mice before LOH occurs in the Men1 locus.