Link between cell-cycle checkpoint deregulation and telomerase activation in glioma progression.

神经胶质瘤进展中细胞周期检查点失调与端粒酶激活之间的联系。

• 批准号: 11671357
• 负责人: UEKI Keisuke
• 金额: $ 2.18万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671357/
• 关键词: glioma; telomerase; p16; adenovirus; cell cycle; genetic alteration

Deregulation of the G1 cell cycle checkpoint, which leads to unregulated proliferation of tumor cells, is presumed to be an essential step for glioma progression toward high-grade gliomas. Another important step is the immortalization of the cells, in which activation of telomerase plays an essential role. Because these two key steps should occur concomitantly in theory, we investigated the correlation of cell cycle checkpoint deregulation and telomerase activity in glioma cells and in glioma samples.p16/CDKN2A gene incorporated in adenovirus vector was transfected into two glioblastoma cell lines, T98G and U251. The telomerase activity measured by the stretch-PCR assay was markedly decreased in u251 cells and completely suppressed in T98G cells, indicating that activation of telomerase may be a consequence of the G1 checkpoint deregulation.We next examined three genetic alterations, p16 deletion, 13q LOH for RB inactivation, and CDK4 gene amplification in various grades of gliomas. At least one of those three genetic alterations was found in 80% of grade4, 20% of grade 3 and 5% of grad2tumors. However, we could detect telomerase activity in only half of grade 4 tumors, and there was no obvious correlation with the genetic alterations. There still is a possibility that difference in sampling procedured may have affected the results, our data were rather negative for the possible correlation of the cell cycle deregulation with the telomerase activation.

G1细胞周期检查点的解除管制，导致肿瘤细胞增殖不受管制，被认为是胶质瘤向高级别胶质瘤发展的必要步骤。另一个重要步骤是细胞的永生化，端粒酶的激活在其中起着至关重要的作用。由于这两个关键步骤在理论上应该同时发生，因此我们研究了胶质瘤细胞和胶质瘤样本中细胞周期检查点解除管制与端粒酶活性的相关性。将p16/CDKN2A基因整合到腺病毒载体中，转染2株胶质母细胞瘤细胞株T98G和U251。拉伸- pcr检测的端粒酶活性在u251细胞中显著降低，在T98G细胞中完全抑制，表明端粒酶的激活可能是G1检查点解除管制的结果。接下来，我们在不同级别的胶质瘤中检测了三种遗传改变，p16缺失，RB失活的13q LOH和CDK4基因扩增。在80%的4级肿瘤、20%的3级肿瘤和5%的2级肿瘤中发现了这三种基因改变中的至少一种。然而，我们只能在一半的4级肿瘤中检测到端粒酶活性，并且端粒酶活性与基因改变没有明显的相关性。仍然有一种可能性，取样程序的差异可能会影响结果，我们的数据是相当消极的细胞周期解除管制与端粒酶激活的可能的相关性。

项目成果

Ueki K: "Molecular genetic markers predicting chemosensitivity of oligodendroglial"neoplasmsMolecular Medicine. 37(suppl.). 149-153 (2000)

Ueki K：“预测少突胶质细胞化学敏感性的分子遗传标记”分子医学。

Ueki K, Chen W, Narita Y, Asai A, Kirino T: "Tight association of merlin loss and loss of heterozygosity of chromosome 22q in sporadic meningiomas"Cancer Res. 59. 5995-5998 (1999)

Ueki K、Chen W、Narita Y、Asai A、Kirino T：“散发性脑膜瘤中 merlin 缺失和 22q 染色体杂合性缺失的紧密关联”Cancer Res。

Smith JS,Tachibana I,Pohl U,Lee HK,Thanarajasingam U,Portier BP,Ueki K,Ramaswamy S,Billings SJ,Mohrenweiser HW,Louis DN,Jenkins RB.: "A transcript map of the chromosome 19 q-arm tumor suppressor region."Genomics. 64. 44-50 (2000)

Smith JS,Tachibana I,Pohl U,Lee HK,Thanarajasingam U,Portier BP,Ueki K,Ramaswamy S,Billings SJ,Mohrenweiser HW,Louis DN,Jenkins RB.：“19 号染色体 q 臂肿瘤抑制因子的转录图

Bauman GS,Ino Y,Ueki K,Zlatescu MC,Fisher BJ,Macdonald DR,Stitt L,Louis DN,Cairncross JG: "Allelic loss of chromosome 1p and radiotherapy plus chemotherapy in patients with oligodendrogiliomas."Int J Radiat Oncol Biol Phys. 48. 825-830 (2000)

Bauman GS、Ino Y、Ueki K、Zlatescu MC、Fisher BJ、Macdonald DR、Stitt L、Louis DN、Cairncross JG：“少突胶质细胞瘤患者的 1p 染色体等位基因丢失和放疗加化疗。”Int J Radiat Oncol Biol Phys。

Pohl U,Smith JS,Tachibana I,Ueki K,Lee HK,Ramaswamy S,Qiang W,Mohrenweiser HW,Jenkins RB,Louis DN: "EHD2,EHD3 and EHD4 encode novelmembers of a highly conserved family of EH domain containing proteins."Genomics. 63. 255-262 (2000)

Pohl U、Smith JS、Tachibana I、Ueki K、Lee HK、Ramaswamy S、Qiang W、Mohrenweiser HW、Jenkins RB、Louis DN：“EHD2、EHD3 和 EHD4 编码包含 EH 结构域的高度保守家族的新成员。”