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MAD2γ是一种新型的MAD2异构体，可减少有丝分裂停滞，并与睾丸生殖细胞肿瘤的耐药性相关。

MAD2γ, a novel MAD2 isoform, reduces mitotic arrest and is associated with resistance in testicular germ cell tumors.

作者信息

López-Saavedra Alejandro, Ramírez-Otero Miguel, Díaz-Chávez José, Cáceres-Gutiérrez Rodrigo, Justo-Garrido Monserrat, Andonegui Marco A, Mendoza Julia, Downie-Ruíz Ángela, Cortés-González Carlo, Reynoso Nancy, Castro-Hernández Clementina, Domínguez-Gómez Guadalupe, Santibáñez Miguel, Fabián-Morales Eunice, Pruefer Franz, Luna-Maldonado Fernando, González-Barrios Rodrigo, Herrera Luis A

机构信息

a Unidad de Investigación Biomédica en Cáncer , Instituto Nacional de Cancerología (INCan) - Instituto de Investigaciones Biomédicas - Universidad Nacional Autónoma de México (UNAM) , Del. Tlalpan , Mexico D.F.

出版信息

Cell Cycle. 2016 Aug 2;15(15):2066-76. doi: 10.1080/15384101.2016.1198863. Epub 2016 Jun 17.

DOI:10.1080/15384101.2016.1198863
PMID:27315568
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4968973/
Abstract

BACKGROUND

Prolonged mitotic arrest in response to anti-cancer chemotherapeutics, such as DNA-damaging agents, induces apoptosis, mitotic catastrophe, and senescence. Disruptions in mitotic checkpoints contribute resistance to DNA-damaging agents in cancer. MAD2 has been associated with checkpoint failure and chemotherapy response. In this study, a novel splice variant of MAD2, designated MAD2γ, was identified, and its association with the DNA damage response was investigated.

METHODS

Endogenous expression of MAD2γ and full-length MAD2 (MAD2α) was measured using RT-PCR in cancer cell lines, normal foreskin fibroblasts, and tumor samples collected from patients with testicular germ cell tumors (TGCTs). A plasmid expressing MAD2γ was transfected into HCT116 cells, and its intracellular localization and checkpoint function were evaluated according to immunofluorescence and mitotic index.

RESULTS

MAD2γ was expressed in several cancer cell lines and non-cancerous fibroblasts. Ectopically expressed MAD2γ localized to the nucleus and reduced the mitotic index, suggesting checkpoint impairment. In patients with TGCTs, the overexpression of endogenous MAD2γ, but not MAD2α, was associated with resistance to cisplatin-based chemotherapy. Likewise, cisplatin induced the overexpression of endogenous MAD2γ, but not MAD2α, in HCT116 cells.

CONCLUSIONS

Overexpression of MAD2γ may play a role in checkpoint disruption and is associated with resistance to cisplatin-based chemotherapy in TGCTs.

摘要

背景

响应抗癌化疗药物（如DNA损伤剂）而导致的有丝分裂长期停滞会诱导细胞凋亡、有丝分裂灾难和衰老。有丝分裂检查点的破坏会导致癌症对DNA损伤剂产生耐药性。MAD2与检查点功能障碍及化疗反应有关。在本研究中，鉴定出一种新型的MAD2剪接变体，命名为MAD2γ，并研究了其与DNA损伤反应的关系。

方法

使用逆转录聚合酶链反应（RT-PCR）检测癌细胞系、正常包皮成纤维细胞以及从睾丸生殖细胞肿瘤（TGCT）患者收集的肿瘤样本中MAD2γ和全长MAD2（MAD2α）的内源性表达。将表达MAD2γ的质粒转染到HCT116细胞中，并根据免疫荧光和有丝分裂指数评估其细胞内定位和检查点功能。

结果

MAD2γ在几种癌细胞系和非癌细胞成纤维细胞中表达。异位表达的MAD2γ定位于细胞核并降低有丝分裂指数，提示检查点功能受损。在TGCT患者中，内源性MAD2γ而非MAD2α的过表达与基于顺铂的化疗耐药相关。同样，顺铂在HCT116细胞中诱导内源性MAD2γ而非MAD2α的过表达。

结论

MAD2γ的过表达可能在检查点破坏中起作用，并与TGCT中基于顺铂的化疗耐药相关。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fcd/4968973/c45cc602b5c7/kccy-15-15-1198863-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fcd/4968973/ee76867e9ac7/kccy-15-15-1198863-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fcd/4968973/bc25b42f9e92/kccy-15-15-1198863-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fcd/4968973/875d5870ae40/kccy-15-15-1198863-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fcd/4968973/d1dd88a16f8b/kccy-15-15-1198863-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fcd/4968973/4858dc2fb304/kccy-15-15-1198863-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fcd/4968973/c01939db20e4/kccy-15-15-1198863-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fcd/4968973/c45cc602b5c7/kccy-15-15-1198863-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fcd/4968973/ee76867e9ac7/kccy-15-15-1198863-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fcd/4968973/bc25b42f9e92/kccy-15-15-1198863-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fcd/4968973/875d5870ae40/kccy-15-15-1198863-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fcd/4968973/d1dd88a16f8b/kccy-15-15-1198863-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fcd/4968973/4858dc2fb304/kccy-15-15-1198863-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fcd/4968973/c01939db20e4/kccy-15-15-1198863-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fcd/4968973/c45cc602b5c7/kccy-15-15-1198863-g007.jpg

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