Ablation of a peptidyl prolyl isomerase Pin1 from p53-null mice accelerated thymic hyperplasia by increasing the level of the intracellular form of Notch1
Ablation of a peptidyl prolyl isomerase Pin1 from p53-null mice accelerated thymic hyperplasia by increasing the level of the intracellular form of Notch1
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DOI：
10.1038/sj.onc.1210153
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发表时间：
2007-05
期刊：
影响因子：
8
通讯作者：
Katsuhiko Takahashi;Katsuhiko Takahashi;H. Akiyama;Kiyoe Shimazaki;C. Uchida;C. Uchida;H. Akiyama-Okunuki;Motowo Tomita;M. Fukumoto;Takafumi Uchida
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文献类型：
--
作者：
Katsuhiko Takahashi;Katsuhiko Takahashi;H. Akiyama;Kiyoe Shimazaki;C. Uchida;C. Uchida;H. Akiyama-Okunuki;Motowo Tomita;M. Fukumoto;Takafumi Uchida
肿瘤抑制基因p53在应对多种基因毒性应激的检查点控制中起着至关重要的作用。DNA损伤导致P53的Ser/Thr-Pro基序的磷酸化，从而促进与Pin1的相互作用，Pin1是一种pSer/pThr-Pro特异性的肽基Pro异构酶。PIN1是P53及时激活所必需的，从而导致细胞凋亡或细胞周期停滞。为了研究PIN1和P53之间的生理关系，我们建立了PIN1−/−P53−/−小鼠。这些P53基因缺陷的小鼠自发地发展为淋巴瘤，主要起源于胸腺，以及广泛的淋巴瘤浸润性到其他器官，包括肝脏，肾脏和肺。除P53外，除PIN1外，PIN1还可加速胸腺的增殖，但这些PIN1−/−P53−/−小鼠的胸腺细胞并未渗入其他器官。12周龄PIN1−/−P53−/−小鼠胸腺细胞为CD4、−、CD8−(双阴性)，细胞内型Notch1(NIC)水平显著高于P53−/−或野生型小鼠胸腺细胞。PIN1−/−-P53−/−小鼠胸腺细胞中NIC生成的裂解酶--早老素-1在PIN1-P53小鼠胸腺细胞中升高。Pin1的缺失也抑制了蛋白酶体对NIC的降解。这些结果表明，Pin1和P53均通过调节NIC水平来调控胸腺细胞的正常增殖和分化。
Tumor suppressor p53 is essential for checkpoint control in response to a variety of genotoxic stresses. DNA damage leads to phosphorylation on the Ser/Thr-Pro motifs of p53, which facilitates interaction with Pin1, a pSer/pThr-Pro-specific peptidyl prolyl isomerase. Pin1 is required for the timely activation of p53, resulting in apoptosis or cell cycle arrest. To investigate the physiological relationship between Pin1 and p53, we created Pin1−/− p53−/− mice. These p53-deficient mice spontaneously developed lymphomas, mainly of thymic origin, as well as generalized lymphoma infiltration into other organs, including the liver, kidneys and lungs. Ablation of Pin1, in addition to p53, accelerated the thymic hyperplasia, but the thymocytes in these Pin1−/− p53−/− mice did not infiltrate other organs. The thymocytes in 12-week-old Pin1−/− p53−/− mice were CD4− CD8−(double negative) and had significantly higher levels of the intracellular form of Notch1 (NIC) than the thymocytes of p53−/− or wild-type mice. Presenilin-1, a cleavage enzyme for NIC generation from full-length Notch1 was increased in the thymocytes of Pin1−/− p53−/− mice. Pin1 depletion also inhibited the degradation of NIC by proteasomes. These results suggest that both Pin1 and p53 control the normal proliferation and differentiation of thymocytes by regulating the NIC level.