Endocrine Abstracts

The importance of cell cycle regulation in pituitary biology has been suggested from the fact that many gene-targeted mouse models of cell cycle mutations develop diverse pituitary pathologies. The retinoblastoma protein (pRb)/cyclin-dependent kinase 4 (Cdk4) pathway, one of the major mitogen-sensor routes in the cell, seems to be critical in the control of pituitary cell proliferation. Both inactivation of pRb or hyperactivation of Cdk4 result in pituitary hyperplasias or tumors in vivo. In addition, the cell cycle inhibitor p27Kip1 also plays crucial roles in maintaining pituitary homeostasis and p27Kip1 mutations strongly cooperate with the alteration of the pRb/Cdk4 pathway. In fact, these molecules or their regulators are frequently altered by both genetic and epigenetic mechanisms in pituitary tumors as well as in other endocrine pathologies. The use of gene-targeted mouse models has allowed us to dissect in vivo the molecular mechanisms behind these mutations. These data is also suggesting potential therapeutic strategies as some of these molecules, such as Cdks, are ‘druggable’ targets. The analysis of these mutations in specific cells in vivo also provides a valuable tool to understand the role of cell cycle regulation in specific pituitary progenitors or putative pituitary stem cells. Thus, whereas most hyperplasias or adenomas are formed of differentiated, hormone-expressing cells, some aggressive pituitary tumors observed in Cdk4/p27Kip1 double mutant mice present small undifferentiated cells positive for stem cell markers. These in vivo studies using mouse models are therefore suggesting that a proper balance between proliferation and differentiation in specific progenitor cells may be necessary to maintain pituitary homeostasis and the deregulation of key cell cycle proteins may be responsible for specific pituitary pathologies.