Editorial
Length Does Not Matter
A New Take on Telomerase Reverse Transcriptase
Wendy A. Goodman, Mukesh K. Jain
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Atherosclerotic lesions, which are considered to be the
single most important contributor to cardiovascular disease, are characterized by tissue-resident macrophages that
propagate local inflammation and tissue destruction
through the production of reactive oxygen intermediates,
proinflammatory cytokines, and matrix metalloproteinases
that degrade and remodel the extracellular matrix.6 Given
the impact of telomere dysregulation on the fundamental
cellular processes involved in inflammation, and the dearth
of knowledge regarding telomerase activity in myeloid
cells, the potential role for telomerase in mediating macrophage dysfunction is an important research area.
Recent work7,8 has begun to unravel this question in the
context of atherosclerosis. In the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Gizard et al8 show
that expression of hTERT and functional activity of telomerase are induced in primary macrophages after proinflammatory signaling (Figure). This finding is in agreement with
numerous studies9,10 showing that lymphocytes selectively
reactivate telomerase in response to environmental activation
cues, such as exposure to antigen. In these studies, researchers showed that expression of hTERT is enhanced after
stimulation through the B- or T-cell receptors, indicating that,
unlike somatic cells, lymphocytes possess the ability to
reactivate telomerase when proliferation is required. Although the role of telomerase in myeloid cells is less well
characterized, Ping et al11 recently showed that telomerase
activity is increased in primary dendritic cells during differentiation from bone marrow precursor cells. Collectively,
these studies indicate that immune cell activation can induce
expression and activity of telomerase.
Immune cell proliferation can be initiated through signaling
events downstream of proinflammatory stimuli, such as oxidized
low-density lipoprotein, lipopolysaccharide, and tumor necrosis
factor ␣, that converge in gene expression pathways, including
nuclear factor (NF)–␬B. In their current article, Gizard et al8
explore the link between inflammation and elevated telomerase
activity in macrophages after cytokine and oxidized low-density
lipoprotein signaling. Their work identifies a novel NF-␬B
response element in the TERT promoter, demonstrating that
TERT is an NF-␬B target gene and suggesting that telomerase
activity can be transcriptionally regulated after cytokine stimulation. In addition, previous work from Akiyama et al12 showed
that NF-␬B regulates telomerase activity posttranslationally
because it mediates hTERT nuclear translocation through a
physical association. Together, the work of Gizard and Akiyama
and colleagues highlights the complexity of telomerase regulation through both transcriptional and posttranslational mechanisms downstream of cytokine stimulation.
he role of telomeres in maintaining genetic stability was
first described by Blackburn1 in 1991. Telomeres and
their associated proteins provide protection against DNA
degradation because 40 to 200 bp of the telomere’s tandem
repeats are lost on each successive cell division, resulting
in the progressive shortening of chromosomes. Telomeres
also help to regulate the “cellular clock” because critically
short telomeres trigger a cell cycle checkpoint, resulting in
replicative senescence (ie, a natural process for terminally
differentiated somatic cells, yet undesirable for hematopoietic cells, which require the potential for regulated
proliferation throughout life).2 Thus, exquisite regulation
of telomerase is required for extension of telomeres under
appropriate conditions in immune cells. Indeed, overexpression or underexpression of telomerase or its reverse
transcriptase catalytic domain, human telomerase reverse
transcriptase (hTERT), is associated with numerous
chronic inflammatory and autoimmune disorders,3 underscoring the importance of telomerase activity in immune
cell function.
See accompanying article on page 245
Nearly 10 years ago, Stewart et al4 demonstrated a novel
role for telomerase in the promotion of tumorigenesis. By
using an hTERT-mutant protein unable to extend telomere
length, the researchers showed that TERT, together with
transforming protein p21 (H-RAS), induced tumorigenesis
independently of effects on telomeres. Adding further
complexity to telomerase activity, recent work from Park
et al5 showed that TERT associates with Brahma-related
gene (BRG-1) to occupy promoter sites of wingless (Wnt)responsive genes, suggesting that TERT may associate
with other transcriptional complexes. The consequences of
this work are far-reaching because they implicate noncanonical mechanisms of telomerase activity in biological
activities, such as cell proliferation and survival. These
noncanonical functions of telomerase are in the spotlight,
especially in the context of chronic inflammatory diseases
such as atherosclerosis, in which proliferation and apoptosis are dysregulated.
From the Cardiovascular Research Institute, Department of Medicine,
Case Western Reserve University, Cleveland, Ohio.
Correspondence to Mukesh K. Jain, MD, Cardiovascular Research
Institute, Department of Medicine, Case Western Reserve University,
2103 Cornell Rd, Room 4537, Cleveland, OH 44106. E-mail
[email protected]
(Arterioscler Thromb Vasc Biol. 2011;31:235-236.)
© 2011 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org
DOI: 10.1161/ATVBAHA.110.220343
235
236
Arterioscler Thromb Vasc Biol
February 2011
Figure. Proinflammatory stimuli, including
oxidized low-density lipoprotein, tumor
necrosis factor ␣, and lipopolysaccharide,
signal to primary macrophages, inducing
activation and translocation of NF-␬B.
NF-␬B–mediated transcription of telomerase reverse transcriptase (tert) leads to
numerous biological effects, including
direct effects on telomeres and noncanonical roles in matrix metalloproteinase production and macrophage activation.
OxLDL indicates oxidized low-density
lipoprotein; TNF␣, tumor necrosis factor ␣;
LPS, lipopolysaccharide; NF␬B, nuclear
factor ␬B; I␬B, inhibitor of ␬B; htert,
human telomerase reverse transcriptase.
Downloaded from http://atvb.ahajournals.org/ by guest on June 18, 2017
Many inflammatory diseases, including atherosclerosis, are
associated with aging. Because aging also correlates with telomere shortening, lowered telomerase activity has been hypothesized to play a causal role in the development of atherosclerosis
and cardiovascular disease.13 Findeisen et al7 suggest that the
role of telomerase may not be so straightforward; they recently
showed that TERT deficiency in bone marrow cells is protective
against the formation of abdominal aortic aneurysm in mice.
Interestingly, protection against aneurysm was associated with
lowered matrix metalloproteinase production by macrophages.
Furthermore, Gizard et al8 demonstrate that TERT is strongly
expressed in human coronary artery atherosclerotic lesions and
that TERT expression colocalizes with the macrophage marker
CD68. Development of atherosclerotic lesions in low-density
lipoprotein receptor⫺/⫺ mice receiving a high-fat diet also
correlated with increased telomerase activity, further implicating
elevated TERT and telomerase activity with the development of
atherosclerosis.
Perhaps not surprisingly, the role of telomerase in inflammation remains a complex issue. Recent work from Bhattacharjee
et al14 has shown that mice lacking TERC, the RNA template for
telomerase transcriptional activity, express elevated levels of
toll-like receptor 4 and are prone to inflammation. Although
these findings may seem contradictory to those of Gizard et al,8
they raise the possibility that certain telomerase activities may
remain intact in mice lacking TERC. Although these noncanonical telomerase functions may not directly involve reverse transcriptase activity, another recent study from Poch et al15 showed
that shortened telomeres are protective against diet-induced
atherosclerosis in apolipoprotein E⫺/⫺ mice. Thus, noncanonical
activities of TERT may not be totally disconnected from
traditional effects on telomeres.
The modulation of telomerase activity represents an attractive therapeutic strategy for numerous diseases, and inhibition
of TERT has already been successfully translated to anticancer therapies.16 Conversely, reactivation of telomerase was
recently shown by Jaskelioff et al17 to reverse systemic
degenerative disease in aged mice. Whether similar therapeutic strategies will prove useful in the treatment of chronic
inflammatory diseases, such as atherosclerosis, remains unknown. Nevertheless, the work of Gizard et al8 marks an
important step toward unraveling the complex role of TERT
in inflammatory diseases.
Disclosures
None.
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KEY WORDS: atherosclerosis
signal transduction
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macrophages
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oxidized lipids
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Length Does Not Matter: A New Take on Telomerase Reverse Transcriptase
Wendy A. Goodman and Mukesh K. Jain
Arterioscler Thromb Vasc Biol. 2011;31:235-236
doi: 10.1161/ATVBAHA.110.220343
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