Yao T P, Oh S P, Fuchs M, Zhou N D, Ch'ng L E, Newsome D, Bronson R T, Li E, Livingston D M, Eckner R
Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
Cell. 1998 May 1;93(3):361-72. doi: 10.1016/s0092-8674(00)81165-4.
The transcriptional coactivator and integrator p300 and its closely related family member CBP mediate multiple, signal-dependent transcriptional events. We have generated mice lacking a functional p300 gene. Animals nullizygous for p300 died between days 9 and 11.5 of gestation, exhibiting defects in neurulation, cell proliferation, and heart development. Cells derived from p300-deficient embryos displayed specific transcriptional defects and proliferated poorly. Surprisingly, p300 heterozygotes also manifested considerable embryonic lethality. Moreover, double heterozygosity for p300 and cbp was invariably associated with embryonic death. Thus, mouse development is exquisitely sensitive to the overall gene dosage of p300 and cbp. Our results provide genetic evidence that a coactivator endowed with histone acetyltransferase activity is essential for mammalian cell proliferation and development.
转录共激活因子兼整合因子p300及其密切相关的家族成员CBP介导多种信号依赖的转录事件。我们构建了缺乏功能性p300基因的小鼠。p300基因纯合缺失的动物在妊娠第9天至11.5天之间死亡，表现出神经胚形成、细胞增殖和心脏发育缺陷。来自p300缺陷胚胎的细胞表现出特定的转录缺陷且增殖能力差。令人惊讶的是，p300杂合子也表现出相当程度的胚胎致死性。此外，p300和cbp的双杂合性总是与胚胎死亡相关。因此，小鼠发育对p300和cbp的整体基因剂量极为敏感。我们的结果提供了遗传学证据，表明具有组蛋白乙酰转移酶活性的共激活因子对哺乳动物细胞增殖和发育至关重要。
