Okuda T, Hirai H, Valentine V A, Shurtleff S A, Kidd V J, Lahti J M, Sherr C J, Downing J R
Department of Pathology, Howard Hughes Medical Institute, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Genomics. 1995 Oct 10;29(3):623-30. doi: 10.1006/geno.1995.9957.
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 kinases in vivo. A new member of the INK4 gene family, murine INK4d, has recently been identified. Here we report the isolation of human INK4d (gene symbol CDKN2D), which is 86% identical at the amino acid level to the murine clone and approximately 44% identical to each of the other human INK4 family members. The INK4d gene 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 of INK4d mRNA oscillates in a cell-cycle-dependent manner with expression lowest at mid G1 and maximal during S phase. Using a P1-phage genomic clone of INK4d for fluorescence in situ hybridization analysis, the location of this gene was mapped to chromosome 19p13. No rearrangements or deletions of the INK4d gene were observed in Southern blot analysis of selected cases of pediatric acute lymphoblastic leukemia (ALL) containing a variant (1;19)(q23;p13) translocation that lacks rearrangement of either E2A or PBX1, or in ALL cases containing homozygous or hemizygous deletions of the related genes, INK4a and INK4b.
细胞周期G1期的进展取决于D型细胞周期蛋白与其催化伙伴细胞周期蛋白依赖性激酶cdk4和cdk6之间形成的全酶的活性。p16INK4a、p15INK4b和p18INK4c是一组结构相关的蛋白质，作为细胞周期蛋白D依赖性激酶的特异性抑制剂发挥作用，并且可能在体内作为这些激酶的特异性调节因子发挥生理作用。INK4基因家族的一个新成员——小鼠INK4d最近已被鉴定出来。在此我们报告人类INK4d（基因符号CDKN2D）的分离，其在氨基酸水平上与小鼠克隆有86%的同一性，与其他人类INK4家族成员中的每一个大约有44%的同一性。INK4d基因以单一的1.4kb mRNA普遍表达，在胸腺、脾脏、外周血白细胞、胎儿肝脏、大脑和睾丸中检测到的水平最高。INK4d mRNA的丰度以细胞周期依赖性方式振荡，在G1期中期表达最低，在S期最大。使用INK4d的P1噬菌体基因组克隆进行荧光原位杂交分析，该基因的位置被定位到19号染色体p13。在对选定的小儿急性淋巴细胞白血病（ALL）病例进行的Southern印迹分析中，未观察到INK4d基因的重排或缺失，这些病例包含缺乏E2A或PBX1重排的变异型（1；19）（q23；p13）易位，或者在包含相关基因INK4a和INK4b纯合或半合子缺失的ALL病例中也未观察到。
