Human Telomerase Reverse Transcriptase (hTERT) Positively Regulates 26S Proteasome Activity

Im, Eunju; Yoon, Jong Bok; Lee, Han Woong; Chung, Kwang Chul

doi:10.1002/jcp.25607

Cited by 23 publications

(14 citation statements)

References 48 publications

(69 reference statements)

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“…The Ub G76V -GFP contained a mutant ubiquitin, which prevented cleavage of the N-terminal ubiquitin from the GFP and served as an anchor for polyubiquitination and degradation 40 . Consequently, Ub G76V -GFP was a good substrate for 26S proteasomedependent proteolysis, and its fluorescence intensity was inversely proportional to proteasome activity 41 . As illustrated in Fig.…”

Section: Alg-2 Enhances the Activity Of The Proteasomementioning

confidence: 99%

ALG-2 couples T cell activation and apoptosis by regulating proteasome activity and influencing MCL1 stability

Zhang

et al. 2020

Cell Death Dis

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T cell homeostasis is critical for the proper function of the immune system. Following the sharp expansion upon pathogen infection, most T cells die in order to keep balance in the immune system, a process which is controlled by death receptors during the early phase and Bcl-2 proteins in the later phase. It is still highly debated whether the apoptosis of T cells is determined from the beginning, upon activation, or determined later during the contraction. MCL1, a Bcl-2 family member, plays a pivotal role in T cell survival. As a fast turnover protein, MCL1 levels are tightly regulated by the 26S proteasome-controlled protein degradation process. In searching for regulatory factors involved in the actions of MCL1 during T cell apoptosis, we found that ALG-2 was critical for MCL1 stability, a process mediated by a direct interaction between ALG-2 and Rpn3, a key component of the 26S proteasome. As a critical calcium sensor, ALG-2 regulated the activity of the 26S proteasome upon increases to cytosolic calcium levels following T cell activation, this consequently influenced the stability of MCL1 and accelerated the T cell "death" process, leading to T cell contraction and restoration of immune homeostasis. Our study provides support for the notion that T cells are destined for apoptosis after activation, and echoes the previous study about the function of ALG-2 in T cell death.

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Section: Alg-2 Enhances the Activity Of The Proteasomementioning

confidence: 99%

ALG-2 couples T cell activation and apoptosis by regulating proteasome activity and influencing MCL1 stability

Zhang

et al. 2020

Cell Death Dis

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“…TERT induction and telomerase activation not only create unlimited cancer cell proliferation potential by stabilizing telomere length (telomere lengthening-dependent), but also cause oncogenic effects independently of the telomere lengthening function. The telomere lengthening-independent functions of TERT, which significantly contribute to cancer initiation or progression, include its effects on mitochondrial and ubiquitin-proteasomal function, DNA damage repair, gene transcription, microRNA (miRNA) expression, RNA-dependent RNA polymerase activity, and epithelial-mesenchymal transition (48)(49)(50)(51)(52)(53)(54)(55)(56). These TERT activities physiologically affect the processes that ultimately lead to cell aging; however, they also drive cancer development by conferring survival, proliferation, motherhood, and invasive phenotypes.…”

Section: -95% Of Cancers (34)mentioning

confidence: 99%

Telomeres and telomerase in oncogenesis (Review)

et al. 2020

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Telomeres are located at the ends of chromosomes and protect them from degradation. Suppressing the activity of telomerase, a telomere-synthesizing enzyme, and maintaining short telomeres is a protective mechanism against cancer in humans. In most human somatic cells, the expression of telomerase reverse transcriptase (TERT) is repressed and telomerase activity is inhibited. This leads to the progressive shortening of telomeres and inhibition of cell growth in a process called replicative senescence. Most types of primary cancer exhibit telomerase activation, which allows uncontrolled cell proliferation. Previous research indicates that TERT activation also affects cancer development through activities other than the canonical function of mediating telomere elongation. Recent studies have improved the understanding of the structure and function of telomeres and telomerase as well as key mechanisms underlying the activation of TERT and its role in oncogenesis. These advances led to a search for drugs that inhibit telomerase as a target for cancer therapy. The present review article summarizes the organization and function of telomeres, their role in carcinogenesis, and advances in telomerase-targeted therapy.

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“…TERT induction/telomerase activation confers unlimited proliferation potential to cancer cells by stabilizing their telomere length, while recent observations reveal its multiple oncogenic activities independently of a telomerelengthening function, which include its effect on mitochondrial and ubiquitin-proteasomal function, DNA damage repair, gene transcription, microRNA expression, etc. [8][9][10][11][12][13][14][15][16]. Importantly, TERT was previously shown to promote the proliferation of normal mouse stem cells by recruiting chromatin-remodeling factor Brg1 to β-catenin target genes for their transcriptional activation [17]; and more recently, TERT was found to directly interact with β-catenin and robustly amplify its transcriptional outputs, thereby stimulating epithelial mesenchymal transformation (EMT) and stemness of cancer cells [12,13].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players

2019

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Long-lived species Homo sapiens have evolved robust protection mechanisms against cancer by repressing telomerase and maintaining short telomeres, thereby delaying the onset of the majority of cancer types until post-reproductive age. Indeed, telomerase is silent in most differentiated human cells, predominantly due to the transcriptional repression of its catalytic component telomerase reverse transcriptase (TERT) gene. The lack of telomerase/TERT expression leads to progressive telomere erosion in dividing human cells, whereas critically shortened telomere length induces a permanent growth arrest stage named replicative senescence. TERT/telomerase activation has been experimentally shown to be essential to cellular immortalization and malignant transformation by stabilizing telomere length and erasing the senescence barrier. Consistently, TERT expression/telomerase activity is detectable in up to 90% of human primary cancers. Compelling evidence has also accumulated that TERT contributes to cancer development and progression via multiple activities beyond its canonical telomere-lengthening function. Given these key roles of telomerase and TERT in oncogenesis, great efforts have been made to decipher mechanisms underlying telomerase activation and TERT induction. In the last two decades since the TERT gene and promoter were cloned, the derepression of the TERT gene has been shown to be achieved typically at a transcriptional level through dysregulation of oncogenic factors or signaling, post-transcriptional/translational regulation and genomic amplification. However, advances in high-throughput next-generation sequencing technologies have prompted a revolution in cancer genomics, which leads to the recent discovery that genomic alterations take center stage in activating the TERT gene. In this review article, we summarize critical mechanisms activating TERT transcription, with special emphases on the contribution of TERT promoter mutations and structural alterations at the TERT locus, and briefly discuss the underlying implications of these genomic events-driven TERT hyperactivity in cancer initiation/progression and potential clinical applications as well.

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Human Telomerase Reverse Transcriptase (hTERT) Positively Regulates 26S Proteasome Activity

Cited by 23 publications

References 48 publications

ALG-2 couples T cell activation and apoptosis by regulating proteasome activity and influencing MCL1 stability

ALG-2 couples T cell activation and apoptosis by regulating proteasome activity and influencing MCL1 stability

Telomeres and telomerase in oncogenesis (Review)

Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players

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