p57(Kip2) regulates T-cell development and lymphoma.

In this issue of Blood, Matsumoto et al report that T cell–specific deletion of the cyclin-dependent kinase inhibitor p57 (p57) in mice leads to a block in T-cell development as a result of hyperactivation of the E2F-p53 pathway and demonstrate that the loss of p57 accelerates lymphomagenesis in the absence of p53. T cells are important components of the adaptive immune system central for cellmediated immunity. All T cells originate from hematopoietic stem cells in the bone marrow and mature in the thymus. T-cell development involves progression of immature thymocytes that are double-negative (DN) for CD4 and CD8 (DN, CD4CD8) to the doublepositive (DP, CD4CD8) thymocytes, which finally mature into single-positive (SP) CD4 or CD8 T cells. The DN thymocytes are further classified based by CD44 and CD25 expression: CD44CD25 (DN1), CD44 CD25 (DN2), CD44CD25 (DN3), and CD44CD25 (DN4). The differentiation of immature thymocytes into mature T cells involves several rounds of cell divisions and massive clonal expansion, indicating critical roles for cell-cycle regulators such as cyclindependent kinases (Cdks) and their inhibitors (CKIs) in T-cell development. For instance, Cdk6 and its cognate partner cyclin D3 are critical for normal thymocyte development at the DN stage and for lymphomagenesis. p57 is an imprinted gene that inhibits Cdk2, Cdk3, and Cdk1 and belongs to the Cdk interacting protein/kinase interacting protein (CIP/KIP) family of Cdk inhibitors (CKIs) that also includes p21 and p27. Germ-line mouse knockouts for p57 die shortly after birth with phenotypes similar to Beckwith-Wiedemann syndrome (BWS) patients. When the p27 gene was knocked-in to the p57 locus in mice, many of the defects displayed by p57 knockouts were corrected, suggesting that the phenotypes of p57 knockout mice are largely attributable to its spatial and temporal expression patterns as well as to differences in the sensitivity of tissues to insufficient inhibition of Cdk activity and cell proliferation. HereMatsumoto et al show that conditional T cell–specific deletion of p57 leads to a differentiation block at the DN3 to DN4 transition, resulting in reduced thymic size and cellularity. The differentiation block and smaller thymic size in the absence of p57 is surprising and important given that p57 is a Cdk inhibitor whose deficiency is expected to promote increased cell proliferation. This supports the emerging notion that the roles of Cdks, cyclins, and Cdk inhibitors are not only limited to regulating cell proliferation but are critical for differentiation and survival in a cell type–specific manner. Matsumoto et al also demonstrate that the defects in thymocytes lacking p57 are caused by hyperactivation of The p57-E2F1-p53 pathway in thymocyte development and lymphomagenesis. p57 regulates E2F1 to control E2F target gene expression and p53 activity during normal thymocyte development. In the absence of p57, increased E2F target expression and p53 hyperactivation contribute to the arrest of thymocyte development at the DN3 to DN4 transition. The developmental arrest of thymocytes lacking p57 is partially rescued by the loss of E2F1. Loss of p53 in thymocytes lacking p57 leads to acceleration of thymic lymphoma development, suggesting that the observed p53 hyperactivation in the absence of p57 executes an important tumor suppressor function in thymocytes. Professional illustration by Marie Dauenheimer.