Molecular Cloning, Expression Pattern, and Chromosomal Localization of Human CDKN2D/INK4d,an Inhibitor of Cyclin D-Dependent Kinases

Progression through the G1 phase of the cell cycle is dependent on the activity of holoenzymes formed between D-type cyclins and their catalytic partners, the cyclin-dependent kinases cdk4 and cdk6. p16INK4a,p15INK4b, and p18INK4c, a group of structurally related proteins, function as specific inhibitors of the cyclin D-dependent kinases and are likely to play physiologic roles as specific regulators of these kinasesin vivo.A new member of the INK4 gene family, murineINK4d,has recently been identified. Here we report the isolation of humanINK4d(gene symbolCDKN2D), which is 86% identical at the amino acid level to the murine clone and ∼44% identical to each of the other human INK4 family members. TheINK4dgene is ubiquitously expressed as a single 1.4-kb mRNA with the highest levels detected in thymus, spleen, peripheral blood leukocytes, fetal liver, brain, and testes. The abundance ofINK4dmRNA oscillates in a cell-cycle-dependent manner with expression lowest at mid G1 and maximal during S phase. Using a P1-phage genomic clone ofINK4dfor fluorescencein situhybridization analysis, the location of this gene was mapped to chromosome 19p13. No rearrangements or deletions of theINK4dgene were observed in Southern blot analysis of selected cases of pediatric acute lymphoblastic leukemia (ALL) containing a variant (1;19)(q23′3) translocation that lacks rearrangement of eitherE2AorPBX1, or in ALL cases containing homozygous or hemizygous deletions of the related genes,INK4aandINK4b.