Zhou X, Suzuki H, Shimada Y, Imamura M, Yin J, Jiang H Y, Tarmin L, Abraham J M, Meltzer S J
Department of Medicine, University of Maryland, Baltimore 21201, USA.
Genes Chromosomes Cancer. 1995 Aug;13(4):285-90. doi: 10.1002/gcc.2870130409.
The genes CDKN2B (MTS2) and CDKN2 (MTS1) encoding the proteins p15 and p16 are both located on chromosomal band 9p21, a locus at which frequent homozygous and heterozygous deletions occur in many primary human tumors, including esophageal carcinoma. CDKN2 and CDKN2B belong to a family of cyclin-dependent kinase 4 inhibitors (INK41) and control cell proliferation during the G1 phase of the cell cycle. Their inactivation may contribute to uncontrolled growth in human cancers. To investigate whether CDKN2B and CDKN2 are involved in esophageal tumorigenesis, we studied homozygous deletion, intragenic mutation, and messenger RNA (mRNA) expression of CDKN2 and CDKN2B in nine esophageal squamous cancer cell lines. Polymerase chain reaction (PCR) amplification revealed that five of the nine cell lines (55%) manifested homozygous deletions of CDKN2B, CDKN2, and/or flanking loci on chromosomal band 9p21. Reverse transcriptase-PCR (RT-PCR) was used to examine CDKN2 and CDKN2B mRNA in the nine cell lines. Lack of CDKN2 and CDKN2B mRNA correlated perfectly with homozygous deletion involving these genes. No subtle intragenic mutations of CDKN2B or CDKN2 were detected by DNA sequencing of their entire coding sequences in any cell lines lacking homozygous deletion. Two of the cell lines manifested homozygous deletions excluding CDKN2; one of these two deletions also excluded CDKN2B. These results suggest that inactivation of CDKN2B and CDKN2 may contribute to the malignant phenotype in esophageal cells and that homozygous deletion may be the predominant mechanism for inactivation of CDKN2B and CDKN2. Alternatively, a gene or genes adjacent to CDKN2B/CDKN2 may constitute the target(s) of deletion at this locus.
编码蛋白p15和p16的基因CDKN2B（MTS2）和CDKN2（MTS1）均位于染色体9p21带上，在包括食管癌在内的许多原发性人类肿瘤中，该位点经常发生纯合和杂合缺失。CDKN2和CDKN2B属于细胞周期蛋白依赖性激酶4抑制剂（INK41）家族，在细胞周期的G1期控制细胞增殖。它们的失活可能导致人类癌症中不受控制的生长。为了研究CDKN2B和CDKN2是否参与食管肿瘤发生，我们研究了9种食管鳞状癌细胞系中CDKN2和CDKN2B的纯合缺失、基因内突变和信使核糖核酸（mRNA）表达。聚合酶链反应（PCR）扩增显示，9种细胞系中有5种（55%）表现出CDKN2B、CDKN2和/或染色体9p21带上侧翼位点的纯合缺失。逆转录聚合酶链反应（RT-PCR）用于检测9种细胞系中的CDKN2和CDKN2B mRNA。CDKN2和CDKN2B mRNA的缺失与涉及这些基因的纯合缺失完全相关。在任何缺乏纯合缺失的细胞系中，通过对其整个编码序列进行DNA测序，未检测到CDKN2B或CDKN2的细微基因内突变。其中两种细胞系表现出不包括CDKN2的纯合缺失；这两种缺失中的一种也排除了CDKN2B。这些结果表明，CDKN2B和CDKN2的失活可能导致食管细胞的恶性表型，并且纯合缺失可能是CDKN2B和CDKN2失活的主要机制。或者，与CDKN2B/CDKN2相邻的一个或多个基因可能构成该位点缺失的靶点。
