Unlike Cdk4 deficiency, Cdk2 deficiency does not affect the homeostasis and function of the neuroendocrine tissues, and does not inhibit menin-associated tumorigenesis. These results are congruent with our previous observation that Cdk2 deficiency does not prevent p27-deficient mice from developing pituitary tumors 40. In sharp contrast, Cdk2 deficiency and Cdk4 deficiency are both inhibitory on HER2/neu- induced murine mammary tumorigenesis 41, 42. The embryonic lethality of Cdk4−/−; Cdk2−/− double mutant mice 43 implies that these two kinases have overlapping function in embryonic tissues as well as in most non-endocrine organs. CDK4 abundantly expressed in islet cells of Men1+/−; Cdk2−/− mice may be sufficient to compensate for the absence of CDK2 during tumorigenesis. It is thought that CDK4 and CDK2 collaborate in phosphorylating the critical substrate RB, sharing different phosphorylation sites on the protein 44. In the present study using the islet cell lines, CDK4 depletion inhibited glucose-stimulated hyperphosphorylation of RB, including Ser780 phosphorylation, and G1-S progression, whereas CDK2 depletion had no effect. Collectively, these data underscore the significance of the CDK4-RB pathway in the control of neuroendocrine cell proliferation. Further investigations are necessary to understand how multiple CDK complexes control phosphorylation of RB at the 16 CDK-consensus sites 44 in neuroendocrine-specific manners, and whether non-RB substrates of CDK4 are involved in MEN1 tumorigenesis.