Endocrine Abstracts

A few years ago a novel multiple endocrine neoplasia syndrome, named MEN type 4 (MEN4), was discovered thanks to studies conducted on a MEN syndrome in the rat (named MENX). Rat and human syndromes are both caused by germline mutations in the Cdkn1b/CDKN1B gene encoding p27Kip1, a putative tumor suppressor which binds to and inhibits cyclin/cyclin dependent kinase complexes, thereby inhibiting cell cycle progression. MEN4 patients carry heterozygous mutations at various residues of p27Kip1 and present with endocrine lesions mainly belonging to a MEN1-like spectrum. Indeed, the most common phenotypic features in mutation carriers are parathyroid and pituitary adenomas. Recently, germline mutations in p27kip1 were also identified in patients with a sporadic presentation of parathyroid adenomas. In vitro functional characterization of several CDKN1B sequence variants identified in MEN4 patients, detected impaired activity of the encoded p27Kip1 mutant proteins (e.g. reduced expression, cytoplasmic mislocalization or poor binding to interaction partners). These results indirectly pinpoint the characteristics of the p27Kip1 protein which are critical for tumor suppression. Although the number of MEN4 patients is still very low, the discovery of this syndrome has demonstrated a novel role for CDKN1B as a tumor susceptibility gene for neuroendocrine tumors. In this lecture, I will review clinical and molecular characteristics of the MEN4 syndrome and the role of p27Kip1 in neuroendocrine tumorigenesis.