Telomerase and Cancer
Kirk A. Landon - AACR Prize for Basic Cancer Research Lecture
Elizabeth H. Blackburn
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California
Telomerase is commonly expressed in human cancer cells.
Increased telomerase expression produces vulnerability of
cancer cells, distinguishing them from normal cells in the
body, although normal cells do also have some active
telomerase. Recent studies also suggest that telomerase is
implicated in tumor progression in unexpected ways. These
observations lead us to investigate the most efficient means of
inhibiting telomerase in cancer cells.
A Brief Review of Telomeres and Telomerase
Telomeres, the ends of the chromosomes, are required to
protect chromosomal ends. A complex set of biological
functions is encompassed in the word ‘‘capping’’ of the ends
of the chromosomes. The telomere, after all, represents a DNA
end, which is at the end of the linear chromosomal DNA, but it
has to be treated in a different way from an accidental DNA
break in a chromosome. Primarily, capping is accomplished
through formation of a specific DNA-protein complex at the
chromosomal terminus.
A popular metaphor for what is involved in capping is that
the telomere acts in a way comparable to an aglet, which is
the end of a shoelace. Like an aglet, the telomere prevents that
end from fraying away. What this means at the molecular
level is that the telomeric DNA contains binding sites for
proteins that protect the end of the chromosome. This was first
shown in a model organism, the ciliate Tetrahymena, and
subsequently in many other organisms. The telomeres consist,
first, of a DNA scaffold composed of a tract of very simple
repeated DNA sequences. In the case of humans, the repeat
sequence T2AG3 is repeated, in tandem, thousands of times at
the end of every chromosome. That sequence tract provides a
molecular scaffold on which binds a set of proteins, about
which much is known. These proteins include DNA
sequence – specific binding proteins and other proteins that
together, in effect, sheathe the chromosome end. The resulting
structure is very dynamic. The proteins come on and off the
telomere with surprising speed. Hence, the telomeric structure
is continually being assembled and disassembled. Further-
more, the underlying DNA is also dynamic, for two reasons.
One reason is that, as was predicted in the 1970s, the known
mechanism of DNA polymerase prevents complete DNA
replication all the way to the ends of the chromosome at every
Received 8/23/05; accepted 8/23/05.
Note: This lecture was presented at the AACR 96th Annual Meeting, April 16-20,
2005, Anaheim, CA
Requests for reprints: Elizabeth H. Blackburn, E-mail: telomer@itsa.ucsf.edu
Copyright D 2005 American Association for Cancer Research.
doi:10.1158/1541-7786.MCR-05-0147
Mol Cancer Res 2005;3(9). September 2005
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Research.
round of replication. Thus, incomplete replication of the
chromosome ends occurs, which, if left unchecked by any
compensatory mechanism, leads to a problem of maintaining
the full-length of chromosomal DNA molecules. The
chromosome ends become progressively shorter, which was
predicted eventually to lead, by some unknown mechanism, to
cells ceasing to divide. The solution to this theoretical
problem was the enzyme telomerase (1). Carol Greider and
I identified the telomerase enzyme first in the ciliated
protozoan Tetrahymena. We used this organism because it
has a large number of telomeres and is a relatively rich source
of telomerase. Telomerase contains an RNA component. The
RNA has a short template sequence that is copied into DNA,
which extends, and thus lengthens, the chromosomal DNA.
We were able to show that this also occurs in vivo. It is this
addition of telomeric DNA in increments to the ends of
chromosomes that offsets and counterbalances the shortening
of chromosome ends.
Telomerase is by nature a reverse transcriptase by virtue of
its action of copying the short RNA template sequence within
the telomerase RNA into DNA; an enzyme that copies RNA
into DNA is by definition a reverse transcriptase. Unlike viral
or retroviral reverse transcriptases, such as that of HIV-1, the
cellular enzyme telomerase specializes in making the multiple
short tandem repeats that are at the ends of chromosomes. The
protein component of telomerase, telomerase reverse transcrip-
tase (TERT), is indeed a protein enzyme and its amino acid
sequence includes reverse transcriptase motifs. However, the
RNA is also critically important to the enzyme action, and not
only because it provides the template. The template is only a
minor part of the entire telomerase RNA molecule. The
telomerase RNA is built into the structure of the core
ribonucleoprotein complex of telomerase, which contains the
protein TERT and the telomerase RNA component. After much
study, it has emerged that the RNAs from evolutionarily diverse
eukaryotes share a common core structure (2). The core
structure includes a conserved pseudoknot, which is one of the
parts of RNA that interact tightly and specifically with the
protein TERT in the enzyme complex. The pseudoknot is also
critically important for the action of telomerase. Thus, the RNA
and the protein of telomerase collaborate in the enzymatic
action. That property also makes telomerase a very unusual
reverse transcriptase.
The ciliated protozoan Tetrahymena thermophila normally
has constitutive telomerase and can continue to proliferate
indefinitely like a cancer cell. We were originally able to show
that if we interfered with the action of telomerase in this
organism, the telomeres gradually became shorter and cells
eventually ceased to divide. Thus, we converted an effectively
immortal, perpetually growing organism into a mortal one by
477
478 Blackburn
the simple action of making its telomerase nonfunctional,
thereby showing that telomerase was important for the
continued maintenance of the telomeres and of cell proli-
feration (3).
Humans also have telomerase. With its different RNA
template sequence, it makes the sequence at the ends of our
chromosomes, T2AG3 repeats, which is very much like that of
some ciliated protozoans, T2G4 repeats. Those T2AG3 repeats
are the critical binding sites for sequence-specific telomeric
protective proteins. Telomerase levels are very highly regulated
in normal human cells. As you might expect, telomerase is
active in human stem cells and in germ line cells. At various
levels, it is also active in other adult human cells, but the levels
are often very low and not enough to sustain telomere length
over a lifetime. In humans, gradual shortening of telomeres is
observed throughout life in many cell types in every part of the
body although the cells have a low level of telomerase. In cell
culture, telomere shortening leads to cell senescence as the
telomeres no longer can sustain a capping structure at the ends
of the chromosomes. In 1998, Bodnar et al. (4) showed in a
sufficiency experiment that forced ectopic overexpression of
telomerase is sufficient to overcome cellular senescence in
culture and maintain the telomeres at a steady length as cells
continue to divide. Although that experiment showed that with
enough telomerase the telomeres can be maintained, the length
at which they are maintained in a cell is the result of a complex
interplay among many different factors. Today, many of those
factors are known, including proteins that aid in binding to the
telomere and protect it from increased by telomerase activity.
In the context of the human body, the fact that the action of
telomerase allows cells to keep multiplying can have different
kinds of consequences. Although in many normal adult human
cell types telomerase is often expressed at very low, sometimes
undetectable, levels, it is clear that telomerase has some
protective role in such normal cells. In the context of cancer
cells, particularly those that are well on the way to a malignant
state, telomerase has cancer-promoting properties. It is in that
latter context that we are interested in intervening in telomerase
action.
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Research.
Intervening in the Action of Telomerase in
Human Cancer Cells
As mentioned previously, if telomerase is present in
sufficient amounts, it permits cells to keep multiplying. And,
indeed, many labs and many groups have now shown that
the apparent increase in telomerase is a common feature of
human tumor cells. This increased expression of telomerase
makes it an attractive target for intervention. We investigated
the effect of telomerase inhibition on cancer cells using two
different approaches.
Forcing Telomerase to Make Mutant Telomeric
DNA in Cancer Cells
The first way of intervening in telomerase action in human
cancer cells exploited the fact that the telomeric DNA makes the
molecular scaffold for the binding of telomere-protective
proteins, which include DNA sequence – specific binding
proteins. As described above, the telomeric DNA sequence is
specified by copying the telomerase RNA template. We mutated
the telomerase RNA template so that now a mutated DNA
sequence was added to the chromosomes, directed by the
mutated template. The mutated sequence could not bind the
DNA sequence – specific protective proteins. Hence, the DNA at
the ends of the chromosomes was effectively naked. This had
the consequence of leaving the telomeric tip uncapped (Fig. 1).
We found that the cellular response to this way of uncapping of
telomeres in cancer cells was a very robust apoptotic response
(Fig. 2). For example, in the earliest experiments we did, we
transfected the mutant template telomerase RNA constructs into
human cancer cell lines and selected for cells that stably
expressed the mutant-template telomerase RNA (5). These
cancer cells already had high levels of telomerase, including
high levels of the normal wild-type telomerase RNA. We were
never able to obtain cells that stably expressed more than just a
low fraction of the mutant-template kind of telomerase RNA.
Yet that small fraction of the total telomerase that contained
the mutant-template telomerase RNA was sufficient to elicit a
robust apoptotic response.
FIGURE 1. Strategy for mutant telomere
synthesis in human cancer cells. An example
of mutated bases in the telomerase RNA and
complementary mutant DNA bases incorpo-
rated into telomeric DNA (red A’s and T’s,
respectively) through copying of the mutant
telomerase template. Lower left, schematic of
the uncapping of telomeres. Ovals and dia-
monds, sequence-specific DNA binding pro-
teins that protect telomeric DNA and cap it;
red, telomerase; blue Xs, mutated telomerase
RNA template and correspondingly mutated
telomeric DNA sequence. Reproduced from
the Proceedings of the National Academy of
Sciences, U.S.A., 2001;98:7982 – 7 by copy-
right permission of the National Academy of
Sciences, U.S.A. (5).
Mol Cancer Res 2005;3(9). September 2005

FIGURE 2. Effects of low-level expression
of mutant-template telomerase RNA in MCF-7
breast cancer cells. Apoptosis was quantified
in clonal lines stably expressing low levels of
a mutant-template telomerase RNA con-
struct, a control wild-type RNA construct, or
parental MCF-7 cells. Reproduced from the
Proceedings of the National Academy of
Sciences, U.S.A., 2001;98:7982 – 7 by copy-
right permission of the National Academy of
Sciences, U.S.A. (5).
Hence, all one needed to do was spike the endogenous
telomerase in the cancer cells with a little mutant-template
telomerase RNA that assembled into the telomerase to make
mutant repeats. The population of cells stably expressing the
various different mutant-template RNAs at low levels could
be cultured, although they grew very slowly. Interestingly,
despite being continually serially passaged for months, we
never observed any reversion or any fast-growing resistant
subpopulations growing out from 80 to 100 different clonal
lines that were followed. We interpret these findings to mean
that as the cells grew, with some probability they would die
by apoptosis. Such cell death is, in effect, a one-way street—
once they make the decision to enter apoptosis, the cells
cannot recover to generate any further daughter cells. Similar
findings were also made in the setting of a simple xenograft
model: When we xenografted human cancer cells expressing
the mutant-template telomerase RNA into a mouse model, we
saw greatly decreased tumor growth and some regression of
the tumors, accompanied by high rates of apoptosis in the
tumors (5).
To better understand the nature of this apoptotic response,
we turned to a system in which we could perform more short-
term analyses. The problem was that previously, the only stable
lines that grew out were those that had expressed extremely low
levels of mutant-template telomerase RNA. Therefore, Shang
Li developed a short-term expression system for mutant-
template telomerase RNA (6). We expressed the telomerase
RNA under a promoter that allowed telomerase to be expressed
and active, even in cell lines that normally do not express any
telomerase. These experiments demonstrated that the telomer-
ase RNA was being expressed in a way that supported its
assembly into functional telomerase. We chose as examples for
study two mutant-template telomerase RNAs, which were
mutated in such a way that they dictated the synthesis of DNA
that would be unable to bind the sequence-specific telomere-
protective proteins. Within a few days, the cell growth rate was
Mol Cancer Res 2005;3(9). September 2005
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Telomerase and Cancer 479
markedly decreased. In contrast, the controls, which received
either a wild-type-template telomerase RNA construct or just
the empty lentiviral vector, grew normally. We did these
experiments in a manner that made the test of the effects as
stringent as possible because we did not include a drug
selection step after infecting the cells with the lentiviral vectors.
Not all cells—only about 90% to 95% of the cells—were
infected. Various lines of evidence showed that the cells that
grew out were those that either did not receive the lentivector
or failed to overexpress the mutant-template telomerase RNA.
For example, we could reinfect those outgrowing cells and
recapitulate the same growth kinetics compared with the
controls for at least three cycles of reinfections. Thus, again,
no evidence was found for any resistant subpopulation of cells
that evade the effect of mutant-template telomerase RNA
expression.
An intriguing aspect of these results was the rapidity of
the cell growth response, which we could now examine and
analyze. The response to mutant-template telomerase RNA is
highly specific for cells that have high levels of telomerase.
This response does not require the telomeres to shorten. We
used a particular cell line, the LOX human melanoma cell line,
which happens to have particularly long telomeres, about 40 kb.
DNA Southern blot experiments, done to examine the length of
the telomeric DNA, showed that there was no bulk shortening
of the telomeres. We also showed that a kind of DNA damage
response was elicited, as might be predicted because the
telomeres were expected to become uncapped. For example,
up-regulation of p21 expression was seen, consistent with a
DNA damage response. To determine whether the telomeres
had become uncapped, we looked for the appearance of DNA
damage foci at telomeres (Fig. 3). For these immunostaining
experiments, we used proteins that are known to accumulate in
DNA damage foci at sites of DNA damage, such as the protein
hRif1. Shang Li and Lifeng Xu showed that when we
expressed the mutant-template telomerase RNA, even as early
480 Blackburn
as 3 or 4 days after infection, DNA damage foci appeared at the
telomeres, as visualized by immunostaining of the telomere-
specific protein TRF2. The mutant-template telomerase RNA
caused uncapping of the telomeres. The slowing of cellular
proliferation did not require the protein p53, which is ordinarily
involved in the responses of cells to DNA damage. One line of
evidence for the lack of p53 protein requirement came from the
use of a p53-null human colon cancer cell line kindly provided
by Dr. Burt Vogelstein. When compared with the parent cell
line, in which the p53 locus is left intact, the responses between
the lines were similar. The p53 response pathway is commonly
abrogated in human cancers. Hence, such a p53-independent
apoptotic response is desirable if one is interested in
intervening in telomerase action as an anticancer approach.
Finally, we observed the same kinds of rapid growth inhibitory
effects in the context of a more in vivo – like setting for tumor
cells. In collaboration with Jerry Cunha’s lab at University of
California, San Francisco, human bladder tumor cells were
xenografted under the renal capsule in a mouse. In control
cells, the wild-type telomerase RNA was introduced, and big
robust tumors formed. The tumors that expressed the mutant-
template telomerase RNA were smaller and much less
vascularized, and the tumors weighed less (6).
This work comprises one approach by which one might
exploit the increased expression of telomerase, which is so
common in cancer cells by forcing them to make toxic
telomeres. Encouragingly, this is effective even with very low
levels of expression of the mutant-template RNAs. We are very
interested in understanding the signaling pathways leading to
the apoptosis, which is under active investigation right now.
Unexpected Short-term Effects of Knocking
Down Telomerase Activity in Cancer Cells
Thus far, everything discussed has related to telomerase
acting in its familiar mode: making telomeric DNA longer.
Curiously, however, the high level of telomerase in the majority
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Research.
of cancer cells—which is typically a couple of orders of
magnitude higher in cancer cells than in the differentiated
normal cells around it—usually does not lead to the cancer cells
having long telomeres. Their telomeres are mostly maintained
at a rather short length; the 40 kb telomeres in LOX melanoma
cells are the exception rather than the rule. Thus, there exists a
puzzle that the abundant telomerase activity is apparently not
there to make long telomeres. We therefore investigated what
happens when you knock down the high levels of telomerase in
human cancer cells. Through this work, we learned, somewhat
to our surprise, that we might also be able to incur a more rapid
effect on cancer cell growth than expected and even change
their cancerous properties in ways that were hitherto unsus-
pected (7).
Inhibition of telomerase activity leads to a very simple
expectation: Failure to counteract telomere shortening, the
result of incomplete DNA replication, would cause the
telomeres to get shorter and shorter and eventually they would
become too short to sustain capping, and some signaling
process would direct the cells to cease multiplying or even
undergo apoptosis. Indeed, that expected result is exactly what
is seen when the telomerase activity in cells is inhibited by, for
example, expressing an excess of a catalytically dead version of
the protein TERT, which, although it can still assemble into the
telomerase ribonucleoprotein complex, forms a complex that is
not catalytically active. This inactive complex swamps out
the endogenous telomerase. A delay ensues, during which
telomeres shorten, before the cells finally cease to grow.
Similarly, using inhibitors of telomerase activity, which prevent
telomeric DNA synthesis but do not affect the level of
telomerase ribonucleoprotein, elicits the same expected time
course of events (Table 1).
We did something somewhat different: We knocked down
the telomerase RNA levels so that now, not only was there less
telomerase enzymatic activity but also the cell was depleted of
telomerase ribonucleoprotein itself. The component of the
FIGURE 3. DNA damage foci accumulate
at a subset of telomeres in cells expressing a
mutant-template telomerase RNA. Immunos-
taining was done for telomere-protective pro-
tein TRF2 (green) and for the DNA damage
response protein hRif1 (red). Note that not all
telomeres (TRF2 spots) overlap with DNA
damage foci, although each of the large DNA
damage focal spots overlaps with one or more
telomeres. Reproduced from The Journal of
Cell Biology, 2004;167:819 – 830 by copyright
permission of The Rockefeller University
Press (10).
Mol Cancer Res 2005;3(9). September 2005

telomerase ribonucleoprotein we targeted for knockdown by
RNA interference (short interfering RNA or siRNA) was the
telomerase RNA. The siRNA was directed against either the
wild-type template sequence or the conserved pseudoknot
structure of human telomerase RNA. We could achieve up to
about 90% knockdown either by using short hairpin siRNAs
expressed in the cells from a lentiviral vector expression
cassette or by treating the cancer cells with the short synthetic
siRNA oligonucleotides with or without modified backbones
(Fig. 4). In all cases, we obtained a surprising result: rapid
inhibition of the growth of human telomerase-positive cancer
cells.
The unexpectedly rapid response to telomerase knockdown
prompted us to carry out many controls to rule out possibilities
such as targets other than the telomerase RNA being
responsible for the effects on cell growth. Satisfied that the
effects indeed resulted specifically from knockdown of the
intended telomerase RNA, we analyzed the effects in multiple
cell lines. In contrast to the effects of mutant-template
telomerase RNA expression on telomerase RNA knockdown,
no telomere shortening or telomere uncapping, or DNA damage
response, accompanied the cell growth rate decrease. Once
again, the effects did not require p53 (7).
Off-Label Telomerase
The rapid response of telomerase-positive cancer cells to an
abrupt depletion of their telomerase despite the lack of telomere
uncapping prompted the hypothesis that these effects were
unrelated to telomere maintenance or telomere function.
Supporting this model, Shang Li, in collaboration with Chris
Haqq and his group at University of California, San Francisco,
showed that global gene expression profile changed within 4
days after the telomerase RNA was knocked down. The effects
were different from the gene expression effects elicited by
mutant-template telomerase RNA expression (7). This new
gene expression profile defined an interesting signature for
telomerase knockdown, marked by diminished expression of
73 genes. These included some intriguing genes, such as cyclin
G2 or CDC27—genes that have been implicated in cell cycle
progression. Integrin aV, which has been implicated in
promoting tumor metastasis, was also suppressed.
Clinically, metastasis is arguably the most important factor
in cancer. That telomerase knockdown produced down-
regulation of a specific subset of genes that included those
implicated in tumor progression properties, such as metastasis,
was intriguing. In collaboration with Mohammed Kashani-
Sabet and his group at University of California, San Francisco,
we examined the effect of telomerase RNA knockdown on
Table 1. Growth Inhibitory Effects of Knocking Down Telomerase in Cancer Cells
Old
Need complete knockdown?
Delayed effect: bulk telomeres decline to critical short length?
Delay dependent on initial telomere length in the cancer cells?
Telomere uncapping has to occur?
NOTE: Comparison of human cancer cell growth inhibitory effects predicted and observed when telomerase enzymatic activity was only inhibited (Old) versus those
observed in cells in which total telomerase RNA levels were knocked down (New).
*Rapid down-regulation of genes promoting cell cycle progression and metastasis.
Mol Cancer Res 2005;3(9). September 2005
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Telomerase and Cancer 481
FIGURE 4. Knockdown of endogenous WT-hTER by a short hairpin
RNA (siRNA) directed specifically against the human WT telomerase RNA
template. Northern blot analysis of RNA extracted from a human cancer
cell line, MCF-7. The human telomerase RNA, a non-mRNA, can be
efficiently knocked down by expression of a short hairpin RNA from
a lentiviral construct. GFP lane, Northern blot analysis of RNA from cells
expressing GFP alone from the control lentiviral vector [adapted from
Li et al. (7)].
metastasis in two in vivo models. The telomerase RNA of
mouse melanoma cells (B16 cells) was targeted using
ribozymes, and the human telomerase RNA in human
melanoma cells was targeted using the siRNA approach
described previously (8). Each ribozyme was delivered
systemically after B16 cells had been introduced into mice by
tail-vein injection. After 30 days, the tumor burden in the lungs,
representing metastatic tumors in the lungs, was quantified. The
ribozyme treatment decreased the metastatic burden.
The rapid inhibition of cell growth seen on knockdown of
telomerase indicated that cancer cells are particularly suscep-
tible to its depletion. This implies that they have become
adapted to their high levels of telomerase. As Bernard
Weinstein (9) has proposed for other signaling pathways in
tumors, cancer cells might be ‘‘addicted’’ to high levels of
telomerase, such that their physiology becomes habituated to it
that when telomerase is withdrawn, a ‘‘cold turkey’’ response is
deleterious to the cell. Clearly, our challenge is to understand
how such a mechanism might work.
An important conclusion of this work is that telomerase
participates in cell responses in ways that do not seem to
involve the telomere itself. Hence, our attempts to intervene in
telomerase action have led us unexpectedly down a new avenue
in which we find telomerase doing things that we never
New
f90% bulk knockdown is enough
Effect is immediate*—as fast as can be measured
Independent of starting telomere length
No uncapping seen
482 Blackburn
expected to see. We are hopeful that these avenues will lead us
to a greater understanding of the biology that is being played
out in the progression to a more malignant state of cancer cells,
particularly metastasis.
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Telomerase and Cancer: Kirk A. Landon - AACR Prize for
Basic Cancer Research Lecture
Elizabeth H. Blackburn

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