Watanabe G, Pena P, Shambaugh G E, Haines G K, Pestell R G
Albert Einstein Cancer Center, Department of Medicine, Bronx, NY 10461, USA.
Brain Res Dev Brain Res. 1998 Jun 15;108(1-2):77-87. doi: 10.1016/s0165-3806(98)00032-7.
The cyclin dependent kinase holoenzymes (CDKs), composed of catalytic (cdk) and regulatory (cyclin) subunits, promote cellular proliferation and are inhibited by cyclin dependent kinase inhibitor proteins (CDKIs). The CDKIs include the Ink4 family (p15Ink4b, p16Ink4a, p18Ink4c, p19Ink4d) and the KIP family (p21Cip1 and p27Kip1). The sustained induction of p21 and p18 during myogenesis implicates these CDKI in maintaining cellular differentiation. Herein we examined the CDK (cyclin D1, cdk5) and CDKI expression profiles during the first 24 days of postnatal rat cerebella development. Cdk5 abundance increased and cyclin D1 decreased from day 9 through to adulthood. The CDKIs increased transiently during differentiation. p27 increased 20-fold between days 4 and 24, whereas p21 rose twofold between 6 to 11 days. p19, p18 and p16 increased approximately two- to threefold, falling to low levels in the adult. Immunostaining of cyclin D1 was localized in the external granular cells, whereas p27, was found primarily in the Purkinje cells. The period of maximal differentiation between days 9 to 13 was associated with a change in p21 and p16 staining from the external granular and Purkinje cells to a primarily Purkinje cell distribution. Protein-calorie malnutrition, which was previously shown to arrest rat cerebella development, reduced cyclin D1 kinase activity and p27 levels. However, p16 and p21 levels were unchanged. We conclude that the CDKIs are induced with distinct kinetics in specific cell types and respond differentially to growth factors during cerebella development, suggesting discrete roles for these proteins in normal cerebella development.
细胞周期蛋白依赖性激酶全酶（CDK）由催化亚基（cdk）和调节亚基（细胞周期蛋白）组成，可促进细胞增殖，并受到细胞周期蛋白依赖性激酶抑制蛋白（CDKI）的抑制。CDKI包括Ink4家族（p15Ink4b、p16Ink4a、p18Ink4c、p19Ink4d）和KIP家族（p21Cip1和p27Kip1）。在肌生成过程中p21和p18的持续诱导表明这些CDKI参与维持细胞分化。在此，我们研究了出生后大鼠小脑发育前24天期间CDK（细胞周期蛋白D1、cdk5）和CDKI的表达谱。从第9天到成年期，cdk5丰度增加而细胞周期蛋白D1减少。CDKI在分化过程中短暂增加。p27在第4天到第24天之间增加了20倍，而p21在第6天到第11天之间增加了两倍。p19、p18和p16增加了约两到三倍，在成年期降至低水平。细胞周期蛋白D1的免疫染色定位于外颗粒细胞，而p27主要在浦肯野细胞中发现。第9天到第13天之间的最大分化期与p21和p16染色从外颗粒细胞和浦肯野细胞向主要是浦肯野细胞分布的变化有关。蛋白质-热量营养不良先前已被证明会阻止大鼠小脑发育，它降低了细胞周期蛋白D1激酶活性和p27水平。然而，p16和p21水平未改变。我们得出结论，CDKI在特定细胞类型中以不同的动力学被诱导，并且在小脑发育过程中对生长因子有不同反应，这表明这些蛋白在正常小脑发育中具有不同的作用。
