MCAF1/AM Is Involved in Sp1-mediated Maintenance of Cancer-associated Telomerase Activity
MCAF1/AM Is Involved in Sp1-mediated Maintenance of Cancer-associated Telomerase Activity
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DOI：
10.1074/jbc.m807098200
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发表时间：
2009-02-20
影响因子：
4.8
通讯作者：
Nakao, Mitsuyoshi
中科院分区：
文献类型：
--
作者：
Liu, Lifeng;Ishihara, Ko;Nakao, Mitsuyoshi
端粒酶维持端粒长度，并与哺乳动物细胞的衰老和永生有关。这种酶的两个基本成分是端粒酶逆转录酶（TERT）和端粒酶RNA成分（由TERC基因编码）。这些端粒酶亚基基因主要由特异性蛋白1 （Sp1）表达。含有mbd1的染色质相关因子1 (MCAF1)，也被称为atfa相关调节剂（AM）和激活转录因子7相互作用蛋白（ATF7IP），介导基因调控，尽管MCAF1的确切功能仍有待阐明。在这里，我们报道MCAF1参与癌细胞中依赖sp1的端粒酶活性维持。MCAF1的两个进化保守结构域直接与Sp1和一般转录装置相互作用。MCAF1或Sp1的选择性缺失使培养细胞中的TERT和TERC基因下调，从而导致端粒酶活性降低。在MCAF1或Sp1缺失的情况下，TERT启动子中RNA聚合酶II和一般转录因子ERCC3的转录活性形式下降。与此一致的是，MCAF1经常在源自不同组织的自然发生的癌症中过度表达。我们的数据表明MCAF1的转录功能促进了Sp1的端粒酶表达，这可能是增殖性癌细胞的共同机制。
Telomerase maintains telomere length and is implicated in senescence and immortalization of mammalian cells. Two essential components for this enzyme are telomerase reverse transcriptase (TERT) and the telomerase RNA component (encoded by the TERC gene). These telomerase subunit genes are known to be mainly expressed by specificity protein 1 (Sp1). MBD1-containing chromatin-associated factor 1 (MCAF1), also known as ATFa-associated modulator (AM) and activating transcription factor 7-interacting protein (ATF7IP), mediates gene regulation, although the precise function of MCAF1 remains to be elucidated. Here, we report that MCAF1 is involved in Sp1-dependent maintenance of telomerase activity in cancer cells. Two evolutionarily conserved domains of MCAF1 directly interact with Sp1 and the general transcriptional apparatus. Selective depletion of MCAF1 or Sp1 down-regulates TERT and TERC genes in cultured cells, which results in decreased telomerase activity. The transcriptionally active form of RNA polymerase II and the general transcription factor ERCC3 decreased in the TERT promoter under the loss of MCAF1 or Sp1. Consistently, MCAF1 is found to be frequently overexpressed in naturally occurring cancers that originate in different tissues. Our data suggest that transcriptional function of MCAF1 facilitates telomerase expression by Sp1, which may be a common mechanism in proliferative cancer cells.