Bai Feng, Pei Xin-Hai, Godfrey Virginia L, Xiong Yue
Lineberger Comprehensive Cancer Center. Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA.
Mol Cell Biol. 2003 Feb;23(4):1269-77. doi: 10.1128/MCB.23.4.1269-1277.2003.
The INK4 family of cyclin-dependent kinase (CDK) inhibitors negatively regulates cyclin D-dependent CDK4 and CDK6 and thereby retains the growth-suppressive function of Rb family proteins. Mutations in the CDK4 gene conferring INK4 resistance are associated with familial and sporadic melanoma in humans and result in a wide spectrum of tumors in mice. Whereas loss of function of other INK4 genes in mice leads to little or no tumor development, targeted deletion of p18(INK4c) causes spontaneous pituitary tumors and lymphoma late in life. Here we show that treatment of p18 null and heterozygous mice with a chemical carcinogen resulted in tumor development at an accelerated rate. The remaining wild-type allele of p18 was neither mutated nor silenced in tumors derived from heterozygotes. Hence, p18 is a haploinsufficient tumor suppressor in mice.
细胞周期蛋白依赖性激酶（CDK）抑制剂INK4家族负向调节细胞周期蛋白D依赖性的CDK4和CDK6，从而保留Rb家族蛋白的生长抑制功能。赋予INK4抗性的CDK4基因突变与人类家族性和散发性黑色素瘤相关，并在小鼠中导致多种肿瘤。虽然小鼠中其他INK4基因的功能丧失导致很少或没有肿瘤发生，但p18（INK4c）的靶向缺失会在生命后期导致自发性垂体肿瘤和淋巴瘤。在这里，我们表明用化学致癌物处理p18基因敲除和杂合小鼠会加速肿瘤发生。在杂合子来源的肿瘤中，p18剩余的野生型等位基因既未发生突变也未沉默。因此，p18在小鼠中是一种单倍体不足的肿瘤抑制因子。
