ATM-DEPENDENT PHOSPHORYLATION OF BRCA1 AND ITS BIOLOGICAL SIGNIFICANCE

BRCA1 的 ATM 依赖性磷酸化及其生物学意义

• 批准号: 12680547
• 负责人: SUZUKI Keiji
• 金额: $ 2.24万
• 依托单位: NAGASAKI UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12680547/
• 关键词: BRCA1; ATM; IONIZING RADIATION; WORTMANNIN

BRCA1 PROTEINS FORM DISCRETE FOCI IN THE NUCLEUS OF UNIRRADIATED NORMAL HUMAN DIPLOID CELLS. IN RESPONSE TO IONIXING RADIATION, BRCA1 PROTEINS RELOCATE AND FORM PUNCTATED FOCI, WHICH ARECLOSELY RELATED TO THOSE FORMED BY RAD50/MREll/NBS1 PROTEINS, BUT IN DIFFERENT LOCALIZATION. BECAUSE P53 ACCUMULATION AND PHOSPHORYLATION WAS SUPPRESSED IN HCC1937, WHICH DOES NOT CONTAIN BRCA1 PROTEIN, IT IS SUGGESTED THAT BRCA1 PROTEINS PLAY A ROLE IN ATM-DEPENDENT SIGNAL TRANSDUCTBRCA1 WAS ALSO FOUND TO COLOCALIZE IN THE CENTROSOMES AFTER X-IRRADIATION. CENTROSOMES ARE THE ORGANELLA, WHICH DUPLICATE DURING CELL CECYLE PROGRESSION THROUGH G1 TO S PHASE. A PAIR OF CENTROSOME FUNCTIONS AS A DIVISION POLAR FROM WHICH SPINDLE FIBERS ARE FORMED. IN HCC1937 CELLS, CENTROSOMAL ABNORMALITY WAS FREQUENTLY DETECTED, SUGGESTING THAT BRCA1 PROTEINS ARE INVOLVED IN CENTROSOMAL STABILITY AFTER IRRADIATION. BECAUSE CENTROSOMAL ABNORMALITY RESULTS IN ANEUPLOIDY OF THE CHROMOSOMES, ATM-DEPEPDENT PHOSPHORYLATION OF BRCA1 PROTEIN MAY SUPPRESS OVER REPLICATION OF THE CENTOROSOMES.

BRCA 1蛋白在未经辐射的正常人二倍体细胞核中形成离散的病灶。BRCA 1蛋白对电离辐射的反应是发生移位并形成点斑，这与RAD 50/MRE 11/NBS 1蛋白形成的点斑密切相关，但定位不同。由于不含BRCA 1蛋白的HCC 1937细胞中P53的积累和磷酸化受到抑制，提示BRCA 1蛋白在依赖于大气的信号转导中起作用。中心体是细胞器，在细胞周期从G1期到S期的过程中进行复制。一对中心体功能，作为形成纺锤纤维的分裂极。在HCC 1937细胞中，经常检测到中心体异常，表明BRCA 1蛋白参与辐射后的中心体稳定性。由于中心体异常导致染色体的非整倍性，BRCA 1蛋白的大气依赖性磷酸化可能抑制中心体的过度复制。

项目成果

Miyakoda M.: "Activation of ATM and phosphorylation of p53 yb heat shock"Oncogene. (印刷中). (2002)

Miyakoda M.：“ATM 的激活和 p53 yb 热休克的磷酸化”Oncogene（出版中）。

Miyakoda M.: "Activation of ATM and phosphorylation of p53 by heat shock"Oncogene. 21. 1090-1096 (2002)

Miyakoda M.：“热休克对 ATM 的激活和 p53 的磷酸化”癌基因。

Suzuki, K.: "Radiation-induced senescence-like growth arrest requires Tp53 function but not telomere shortening"Radiation Research. 155. 248-253 (2001)

Suzuki, K.：“辐射诱导的衰老样生长停滞需要 Tp53 功能，但不需要端粒缩短”辐射研究。

Ghosh J.C.: "Dose-dependent biphasic accumulation of Tp53 protein in normal human embryo cells after X irradiation"Radiation Research. 153. 305-311 (2000)

Ghosh J.C.：“X 辐射后正常人胚胎细胞中 Tp53 蛋白的剂量依赖性双相积累”辐射研究。

Ghosh J. C.: "Dose-dependent biphasic accumulation of Tp53 protein in normal human embryo cells after X irradiation"Radiation Research. 153. 305-311 (2000)

Ghosh J. C.：“X 辐射后正常人胚胎细胞中 Tp53 蛋白的剂量依赖性双相积累”辐射研究。