端粒酶通过合成端粒，维持端粒长度和基因组稳定性，在衰老和肿瘤发生过程中发挥关键作用。越来越多的证据显示端粒酶催化亚基具有不依赖端粒酶活性的重要的生物学功能。我们主要研究人端粒酶催化亚基hTERT和它的结合蛋白对一些信号通路和基因转录调控的影响。NF-κB通路是在细胞中广泛存在的信号通路，调控多种靶基因的表达，受多种生理或病例条件下的刺激激活。我们发现过表达人端粒酶催化亚基hTERT和没有端粒酶活性的突变形式K626A能上调金属基质蛋白酶MMP9的表达，并且这种调控依赖MMP9启动子上的NF-κB结合位点。我们进一步发现hTERT和hTERT K626A与NF-κB通路的核心转录因子p65相互作用，促进p65在细胞核中的积累，促进p65与DNA的结合。这些结果证明hTERT是一种重要的NF-κB通路的调控蛋白，hTERT可能通过调控NF-κB通路的活性来促进肿瘤的发生。转录因子Sp1在细胞中普遍存在，被认为是一种组成型的激活因子，调控看家基因和缺少TATA Box的基因。最近研究发现Sp1也能诱导型调控一些基因的表达。Sp1的转录活性受多种翻译后修饰的调控，也受其结合蛋白的调控。我们发现过表达人端粒酶催化亚基hTERT和没有端粒酶活性的突变形式K626A能上调血管内皮生长因子VEGF的表达，hTERT对VEGF的调控作用依赖VEGF启动子上的Sp1结合位点。hTERT和hTERT K626A能与转录因子Sp1相互作用。hTERT与Sp1相互作用，与Sp1一起结合在VEGF启动子上的GC Box上，调控VEGF的表达。hTERT通过上调VEGF的表达促进人脐静脉内皮细胞HUVEC细胞管腔结构的形成。这些结果表明hTERT可以作为转录因子Sp1的共激活因子调控VEGF的表达。hTERT通过上调VEGF的表达，在正常细胞和肿瘤细胞的血管再生过程中发挥重要作用。端粒酶催化亚基的结合蛋白DDRGK1是包含DDRGK结构域蛋白家族的成员，其功能研究很少。IκBα是NF-κB通路中的关键调控蛋白，多种IκBα结合蛋白参与调控NF-κB通路的活性。我们发现用RNA干扰的方法沉默DDRGK1后抑制细胞的增殖和侵袭能力。mRNA表达谱芯片分析发现沉默DDRGK1后多个NF-κB通路的下游靶基因表达下降。我们进一步发现DDRGK1与IκBα的N端相互作用，影响IκBα的磷酸化过程，进一步影响IκBα的泛素化降解。DDRGK1通过调控IκBα的稳定性，影响NF-κB活性。我们的结果证明DDRGK1是一种重要的NF-κB通路的调控蛋白。

Telomerase plays a pivotal role in the pathology of aging and cancer by controlling telomere length and integrity. However, accumulating evidence indicates that telomerase reverse transcriptase (hTERT) may have fundamental biological functions independent of its enzymatic activity in telomere maintenance. In this study, we have characterized several hTERT inetacting proteins and investigated their involvements in gene transcriptional regulation by interacting with hTERT. NF-κB is a ubiquitously expressed transcription factor that regulates a large number of genes in response to diverse physiological and pathological stimuli. We found that the ectopic expression of human telomerase reverse transcriptase (hTERT) and its catalytic mutant hTERT K626A induced MMP9 mRNA expression and promoter activity in an NF-κB-dependent manner. hTERT and hTERT K626A also regulated the expression of several NF-κB target genes in cancer cell lines. Furthermore, both hTERT and hTERT K626A interacted with p65 and increased p65 nuclear accumulation and DNA binding. Together, these data reveal a telomere independent role for telomerase as a transcriptional modulator of the NF-κB signaling pathway and a possible contributor to cancer development and progression.The transcription factor Sp1 is a constitutive activator of many housekeeping genes and some TATA-less genes. However, accumulating evidence indicates that Sp1 regulates gene expression in an inducible manner. The transcriptional activity of Sp1 is regulated by post-translational modifications and by its interaction proteins. We found that the ectopic expression of hTERT and hTERT K626A induced VEGF mRNA expression and promoter activity in an Sp1 dependent manner. Both hTERT and hTERT K626A interacted with Sp1 and increased Sp1 transcription activity. Furthermore, hTERT promoted the tube formation in HUVEC cells through increasing VEGF expression. These data reveal that telomerase can be as a co-activator of the transcription factor Sp1 and a possible contributor to angiogenesis in normal and cancer cells.hTERT binding protein DDRGK1 is a member of the DDRGK domain-containing protein family with unknown function. The regulation of the transcriptional activity of NF-κB is often dependent on its interaction with IκBα. Proteins that bind to IκBα are critical regulators of NF-κB activity. We showed that the depletion of DDRGK1 inhibited cell proliferation and invasion. Microarray analysis indicated that the expression of NF-κB target genes showed the most significant decrease after depleting of DDRGK1, suggesting that DDRGK1 may play an important role in the NF-κB signaling pathway. We further demonstrated that DDRGK1 interacted with IκBα and regulated its stability, thereby regulated the NF-κB transcriptional activity. Our findings identify DDRGK1 as an important regulator of the NF-κB pathway. The biological significance of the interaction between hTERT and DDRGK1 in telomere biology and in the NF-κB pathway warrants a future investigation.