Expression of mTert in primary murine cells links the growth-promoting effects of telomerase to transforming growth factor-β signaling

Geserick, Christoph; Tejera, Águeda M.; González‐Suárez, Eva; Klatt, Peter; Blasco, Marı́a A.

doi:10.1038/sj.onc.1209465

Cited by 63 publications

(54 citation statements)

References 70 publications

(77 reference statements)

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“…The fact that TERT acutely causes profound changes in gene expression in mouse skin supports this idea and indicates that TERT is directly or indirectly associated with gene regulation. Interestingly, stable overexpression of TERT in cell culture, including human mammary epithelial cells, mouse ES cells, and MEFs also led to a specific transcriptional response [41][42][43]. Several aspects of our analyses indicate that the TERT signature defined here represents a coherent, coordinated genetic program.…”

Section: Tert As a Developmental Regulator Controlling Gene Expressionmentioning

confidence: 82%

TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program

Choi¹,

Southworth²,

Sarin³

et al. 2005

PLoS Genet

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Telomerase serves a critical role in stem cell function and tissue homeostasis. This role depends on its ability to synthesize telomere repeats in a manner dependent on the reverse transcriptase (RT) function of its protein component telomerase RT (TERT), as well as on a novel pathway whose mechanism is poorly understood. Here, we use a TERT mutant lacking RT function (TERT ci ) to study the mechanism of TERT action in mammalian skin, an ideal tissue for studying progenitor cell biology. We show that TERT ci retains the full activities of wild-type TERT in enhancing keratinocyte proliferation in skin and in activating resting hair follicle stem cells, which triggers initiation of a new hair follicle growth phase and promotes hair synthesis. To understand the nature of this RT-independent function for TERT, we studied the genome-wide transcriptional response to acute changes in TERT levels in mouse skin. We find that TERT facilitates activation of progenitor cells in the skin and hair follicle by triggering a rapid change in gene expression that significantly overlaps the program controlling natural hair follicle cycling in wild-type mice. Statistical comparisons to other microarray gene sets using pattern-matching algorithms revealed that the TERT transcriptional response strongly resembles those mediated by Myc and Wnt, two proteins intimately associated with stem cell function and cancer. These data show that TERT controls tissue progenitor cells via transcriptional regulation of a developmental program converging on the Myc and Wnt pathways.

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Section: Tert As a Developmental Regulator Controlling Gene Expressionmentioning

confidence: 82%

TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program

Choi¹,

Southworth²,

Sarin³

et al. 2005

PLoS Genet

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“…The protective effect of telomerase against a variety of apoptosisor senescence-inducing stressors has been related to TERT-mediated regulation of expression of genes implicated in cell proliferation and differentiation (Geserick et al, 2006), to improved DNA damage repair (Sharma et al, 2003;Smith et al, 2003), increased apoptosis resistance (del Bufalo et al, 2005;Zhang et al, 2003) or decreased apoptosis signalling (Dudognon et al, 2004). We show here evidence for the existence of a candidate protective mechanism that might be able to integrate some of these observations into a common concept: cells that overexpress TERT show evidence for improved mitochondrial function, specifically less mitochondrial superoxide production and lower levels of cellular ROS, improved mitochondrial coupling and suppressed retrograde response.…”

Section: Discussionmentioning

confidence: 99%

Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress

Ahmed

Passos

Birket

et al. 2008

Journal of Cell Science

430

431

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Telomerase is a ribonucleoprotein that counteracts telomere shortening and can immortalise human cells. There is also evidence for a telomere-independent survival function of telomerase. However, its mechanism is not understood. We show here that TERT, the catalytic subunit of human telomerase, protects human fibroblasts against oxidative stress. While TERT maintains telomere length under standard conditions, telomeres under increased stress shorten as fast as in cells without active telomerase. This is because TERT is reversibly excluded from the nucleus under stress in a dose- and time-dependent manner. Extranuclear telomerase colocalises with mitochondria. In TERT-overexpressing cells, mtDNA is protected, mitochondrial membrane potential is increased and mitochondrial superoxide production and cell peroxide levels are decreased, all indicating improved mitochondrial function and diminished retrograde response. We propose protection of mitochondria under mild stress as a novel function of TERT.

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“…Transgenic mice overexpressing mTERT in keratinocytes have an increased incidence of carcinogen-induced epidermal tumors and improved wound healing (6). Ectopic telomerase expression can also confer resistance to antiproliferative and proapoptotic stimuli (18)(19)(20)(21) and enhance proliferation of diverse cell types such as mouse embryonic fibroblasts (18), cardiac myocytes (22), and human fibroblasts (23). Furthermore, hTERT can function as a RNA-dependent RNA polymerase that can bind to non-hTR RNAs, such as the RNA component of mitochondrial RNA processing endoribonuclease (RMRP), and use them as templates to generate double-stranded RNAs that are processed into siRNAs (24).…”

mentioning

confidence: 99%

Separation of telomerase functions by reverse genetics

Mukherjee

Firpo

Wang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The canonical function of the human telomerase protein (hTERT) is to synthesize telomeric DNA, but it has other biological activities, including enhancing cell proliferation, decreasing apoptosis, regulating DNA damage responses, and increasing cellular proliferative lifespan. The mechanistic relationships among these activities are not understood. We previously demonstrated that ectopic hTERT expression in primary human mammary epithelial cells diminishes their requirement for exogenous mitogens, thus giving them a proliferative advantage in a mitogen-depleted environment. Here, we show that this phenotype is caused by a combination of increased cell division and decreased apoptosis. In addition, we use a panel of hTERT mutants to demonstrate that this enhanced cell proliferation can be uncoupled not only from telomere elongation, but also from other telomerase activities, including cellular lifespan extension and regulation of DNA damage responses. We also find that the proliferative function of hTERT, which requires hTERT catalytic activity, is not caused by increased Wnt signaling, but is accompanied by alterations in key cell cycle regulators and is linked to an hTERT-catalyzed decrease in the levels of the RNA component of mitochondrial RNA processing endoribonuclease. Thus, enhanced cell proliferation is an independent function of hTERT that could provide a new target for the development of anti-telomerase cancer therapeutic agents.

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Expression of mTert in primary murine cells links the growth-promoting effects of telomerase to transforming growth factor-β signaling

Cited by 63 publications

References 70 publications

TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program

TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program

Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress

Separation of telomerase functions by reverse genetics

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