p21 delays tumor onset by preservation of chromosomal
p21 delays tumor onset by preservation of chromosomal
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DOI：
10.1073/pnas.0606343104
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发表时间：
2006-12-26
影响因子：
11.1
通讯作者：
Lozano, Guillermina
中科院分区：
文献类型：
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作者：
Barboza, Juan A.;Liu, Geng;Lozano, Guillermina
P53蛋白通过启动细胞功能，如细胞周期停滞和细胞凋亡来抑制肿瘤的发生，以应对DNA损伤。P53突变体p53R172P缺乏细胞凋亡，但保留了部分细胞周期停止功能，可推迟小鼠肿瘤的发生。值得注意的是，发生在Trp53(515C/515C)小鼠(编码p53R172P)的淋巴瘤保持了稳定的基因组。鉴于p21在p53细胞周期控制中的主导作用，我们将TP53(51SC/515C)小鼠置于p21缺失的背景中，以确定p21是否是维持染色体稳定和延迟肿瘤发生所必需的。P21的缺失完全取消了p53R172P的细胞周期停滞功能，加速了Trp53(515C/515C)小鼠的肿瘤发生。对TrP53(515C/515)、cp21(-/-)肉瘤和淋巴瘤进行细胞遗传学检查，发现TrP53(515C/515C)恶性肿瘤中不存在非整倍体和染色体异常。因此，p21结合了p53依赖的检查点控制和维持染色体的稳定性，并与细胞凋亡协同抑制小鼠肿瘤的发生。
The p53 protein suppresses tumorigenesis by initiating cellular functions such as cell cycle arrest and apoptosis in response to DNA damage. A p53 mutant, p53R172P, which is deficient for apoptosis but retains a partial cell cycle arrest function, delays tumor onset in mice. Remarkably, lymphomas arising in Trp53(515C/515C) mice (encoding p53R172P) retain stable genomes. Given the dominant role of p21 in p53 cell cycle control, we crossed Tp53(51SC/515C) mice onto a p21-null background to determine whether p21 was required for maintaining chromosomal stability and delaying tumor onset. Loss of p21 completely abolished the cell cycle arrest function of p53R172P and accelerated tumor onset in Trp53(515C/515C) mice. Cytogenetic examination of Trp53(515C/515) cp21(-/-) sarcomas and lymphomas revealed aneuploicly and chromosomal aberrations that were absent in Trp53(515C/515C) malignancies. Thus, p21 coupled p53-dependent checkpoint control and preservation of chromosomal stability, and cooperated with apoptosis in suppressing tumor onset in mice.