bluuebunny/crossref_metadata_2025_split huggingface dataset:
Napoleonic Demons: Short telomeres trigger trouble for everyone
Authors: Strauss Evelyn 
Published: August 2003

Like mischievous teenagers on a train, small numbers of telomeres can pull an emergency cord and stop the cell that carries them. These repeated stretches of DNA and associated proteins cap chromosome ends and play a key role in cellular life and death. When telomeres decay, chromosomes fuse with each other and spark genetic havoc that can lead to cancer (see
"Intimate Liaisons"
) or induce a cell to commit suicide (see
"More Than a Sum of Our Cells"
). The consequences of telomere dysfunction are well established, but the exact trigger remains unknown. Several groups have studied the relation between cell survival and average telomere length. As a result, some investigators have concluded that telomeric length does not solely govern its function, because the cell can act up even when the average length remains generous. But new work shows that cells respond to individual chromosome ends rather than the average: Even a small number of shrunken telomeres can spur lethal events.

Hemann and colleagues generated mice with very short telomeres by inbreeding for six generations animals that lack telomerase, the enzyme that replenishes the short repeated sequences that compose telomeric DNA. Then they mated individuals from this strain with those with normal telomeres. The resulting offspring have long telomeres on half of their chromosomes and short ones on the other half. If average telomere length determines survival, the extent of cell suicide--or apoptosis--in these mice should fall halfway between that of the two parents. To probe this issue, the team analyzed cell death and found instead that the degree of apoptosis resembles that of the parent with short telomeres. This result suggests that the most diminutive telomeres--not the whole population--sabotage cells.
To find out whether the shriveled ends instigate global telomere trouble--inducing normal ends to inappropriately stick together, for example--the researchers assessed the relation between telomere length and misconduct. They used a fluorescent probe consisting of dye-labeled DNA that binds to the repeated sequences and emits a signal whose intensity is proportional to telomere length. Using this technique, they showed that chromosomes that most frequently fuse carry the shortest telomeres; chromosomes with long telomeres tend to behave properly.
Together, the results suggest that small numbers of miscreant telomeres set off the cellular alarms that lead to death. Apparently, although most telomeres are good passengers, a few deviants can slam on the brakes for the entire cell.
--Evelyn Strauss

M. T. Hemann, M. A. Strong, L.-Y. Hao, C. W. Greider, The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability.
Cell
107
, 67-77 (2001).
[Abstract]
[Full Text]
Faustian Bargain: Cellular senescence at first prevents, later promotes, cancer
Authors: Davenport R. John 
Published: August 2003

What seems like a good idea can sometimes backfire later. A mechanism that foils cancer in young animals might induce it in older ones, according to a new study.

Most mammalian cells, whether in animals or culture dishes, don't divide forever; instead, they eventually undergo cellular senescence, which permanently arrests cell division (see
"More Than a Sum of Our Cells"
). In animals, that process might prevent cells with DNA damage or shortened telomeres from growing into tumors (see
"Dangerous Liaisons"
). Senescent cells, however, remain in the body--dormant but perhaps not benign.

To investigate how senescent cells affect the tissue in which they reside, Krtolica and colleagues grew cultures that contained either presenescent or senescent fibroblasts--cells that compose connective tissue--and then layered test cultures of various epithelial cell types on top of the fibroblasts. The researchers measured proliferation of the epithelial cells by tagging their DNA with fluorescent labels. Senescent, but not presenescent, fibroblasts provoked duplication of cell lines that had previously acquired mutations known to predispose them to cancer, the team found. Neither senescent nor presenescent fibroblasts promoted the growth of normal human epithelial cells. Cell-to-cell contact isn't required for the stimulation: Material secreted by senescent cells induced precancerous cells to grow approximately three times faster than did material secreted by presenescent cells. Senescent cells also appear to promote tumor growth in vivo: Tumors were more prevalent and grew larger in mice injected with precancerous epithelial cells and senescent fibroblasts than in those injected with precancerous cells and presenescent fibroblasts.
Senescent cells apparently create a rich environment for tumor growth. This phenomenon, combined with the increased incidence of cancer-causing mutations as time passes, could partially explain the exponential increase in cancer rates as we age. Identifying exactly how senescent cells create fertile ground for cancer might well shed light on how a good deal in youth turns sour with age.
--R. John Davenport; suggested by Nick Bishop

A. Krtolica, S. Parrinello, S. Lockett, P.-Y. Desprez, J. Campisi, Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging.
Proc. Natl. Acad. Sci. U.S.A.
98
, 12072-12077 (2001).
[Abstract]
[Full Text]
Keeping the Bad Guy Down: New potential tumor-suppressor gene
Authors: Beckman Mary 
Published: August 2003

In the good guy-bad guy world of cancer, shifty proteins often run afoul of cellular law, prompting molecular sheriffs to action. One cellular citizen--the protein Akt--normally lives a quiet life, performing its civic duty in the insulin-like growth factor-1 (IGF-1) and insulin mammalian signaling pathways. These pathways manage cell growth in mammals, and related ones regulate aging in organisms that include worms, flies, and possibly mice (see
"Growing Old Together"
).

To do its job, Akt slips on a phosphate group. If the protein dons this black hat for too long, however, it triggers a molecular stampede in the IGF-1 signaling pathway, which promotes a half-dozen cancers. Mutations in Akt or its handlers can turn Akt to a permanent life of crime. A corrupt form of the protein, found in many cancers, never removes its phosphate; this version transforms innocuous cell lines into deadly tumor inducers in mice. In healthy cells, a white-hatted cellular cowboy--a tumor-suppressor gene known as
PTEN
--keeps Akt in check. Research has now uncovered a second marshal in the mammalian struggle against unrestrained Akt that keeps the phosphate hat away from the potential scoundrel, preventing it from suiting up in its gunslinger garb.

To seek regulators of Akt, Hemmings and colleagues used a technique to fish out molecules that bind to a bait protein--in this case, a piece of Akt--from a pool of human proteins. Using a variety of biochemical techniques, they showed that one protein--which they named CTMP--prevents Akt from acquiring the phosphate group that leads to its hyperactivity. They then produced CTMP in a cell line made cancerous by the delinquent Akt. CTMP quashed the ability of these cells to grow uncontrolled in culture dishes and reduced the speed at which they induce tumors in mice. These results suggest a rationale for new cancer therapies: Perhaps a drug that mimics CTMP could wrangle in a lawless Akt. The researchers also found that the amount of CTMP in cells mirrored that of PTEN and propose that the two might be regulated in parallel. If so, CTMP could be partly responsible for Akt lawlessness that is now blamed on a slacking PTEN.
CTMP provides a new focus for labs that are trying to discover how IGF-1-like signaling pathways control life-span. Perhaps this molecular desperado plays a role not just in cancer but also in longevity: It might help decide whether to send cells--or organisms--riding off into the sunset.
--Mary Beckman

S.-M. Maira, I. Galetic, D. P. Brazil, S. Kaech, E. Ingley, M. Thelen, B. A. Hemmings, Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane.
Science
294
, 374-380 (2001).
[Abstract]
[Full Text]
Emergency Response Teams Share Strategies: Human and rat brains reorganize similarly after stroke
Authors: Miller Katharine 
Published: August 2003

The human brain behaves like a close-knit community. When natural disaster destroys a few houses, friends across town as well as those next door lend a hand. Similarly, in a stroke-damaged human brain, the uninjured hemisphere tries to help, and later the neighborhood around the hardest hit region recovers enough to pitch in as well. Now, researchers have used functional magnetic resonance imaging (fMRI)--the same technique that uncovered this behavior in human brains--to show that rats' brains reorganize similarly after stroke. Functional magnetic resonance imaging of rat brains after stroke offers a new experimental model for studying how the brain repairs itself and for evaluating therapies.
Dijkhuizen and colleagues induced a stroke in rats by tying off an artery in the right side of the animals' brains; as a result, the left side of the body became temporarily clumsy. They then exploited fMRI to assess how the brains changed as the rats' disabled left limbs recovered. This technique measures blood flow, a reflection of metabolic activity; fMRI generates information about which regions of the brain respond when the subject performs a task. While the animals slept inside the fMRI machine, the researchers gently shocked the rats' left paws to simulate the task of tapping fingers. Three days after the stroke, the brains of sham-operated rats responded on the side opposite the injured limb, but the damaged rats' brains lit up on the unharmed left side. After 14 days, when the animals had regained some control over their left paws, the brightness of the unaffected hemisphere dwindled; the edges of the lesion, however, glowed for the first time.
Functional magnetic resonance imaging provides a noninvasive way to pinpoint sites of physiological change that occur during recovery from a stroke. Because rat and human brains appear to share healing strategies, researchers are optimistic that the new system will provide an experimental model in which to study stroke and its potential treatments. They hope to develop new approaches, because the two therapies currently available are not always effective: Clot-busting drugs work only if used in the first few hours after the mishap, and physical therapy doesn't succeed in all patients. For the approximately 4 million Americans who live with stroke-related disabilities, innovative therapies offer hope of regaining control over their bodies and minds--and toward that end, neighborly rats might now lend a paw.
--Katharine Miller

R. M. Dijkhuizen, J. Ren, J. B. Mandeville, O. Wu, F. M. Ozdag, M. A. Moskowitz, B. R. Rosen, S. P. Finklestein, Functional magnetic resonance imaging of reorganization in rat brain after stroke.
Proc. Natl. Acad. Sci. U.S.A.
98
, 12766-12771 (2001).
[Abstract]
[Full Text]
Protective Pas de Deux? A new partner might help Werner syndrome protein safeguard the genome during replication
Authors: Davenport R. John 
Published: August 2003

The protein that causes the premature aging disorder Werner syndrome (see
"Of Hyperaging and Methuselah Genes"
) has picked up a fresh dance partner. The Werner syndrome protein (WRN) apparently enhances the moves of an enzyme that plays a role in DNA replication and repair. WRN was already known to bind to other proteins involved in these processes, and on its own, it unwinds and chews up DNA. But exactly what WRN does in the cell--and how its defective versions lead to premature aging--remains mysterious.

A protein called FEN-1 trims DNA tails that crop up during DNA replication and repair. In addition, the yeast version of FEN-1 helps maintain genetic stability; a defective form of it provokes genetic mayhem, such as large deletions, also seen in cells with faulty WRN. Because FEN-1 and WRN seem to inspire similar choreography, Brosh and colleagues wondered whether the two ever engage in a molecular tango. To find out, the researchers used a fragment of the WRN protein as bait to fish associated proteins out of material from human cell nuclei. Employing antibodies, they hauled WRN from the mixture and discovered that FEN-1 came along for the ride.
They then probed whether the union between the proteins affects their respective enzymatic activities. Although FEN-1 does not alter WRN's capacity to unwind DNA, WRN stimulates FEN-1's ability to cleave DNA: FEN-1 nibbles DNA faster when WRN is present than when FEN-1 tackles the chore by itself. Whether FEN-1 and WRN perform this duet in intact cells--and whether disrupting this collaboration is a critical trigger for Werner syndrome--remains to be seen. But the result offers a glimpse at some new variations in the Werner protein's repertoire.
--R. John Davenport; suggested by Matt Kaeberlein

R. M. Brosh Jr., C. von Kobbe, J. A. Sommers, P. Karmakar, P. L. Opresko, J. Piotrowski, I. Dianova, G. L. Dianov, V. A. Bohr, Werner syndrome protein interacts with human flap endonuclease 1 and stimulates its cleavage activity.
EMBO J.
20
, 5791-5801 (2001).
[Abstract]
[Full Text]
Bye-bye Birdie: Short-lived fryers less resistant to molecular pecking than long-lived fliers
Authors: Davenport R. John 
Published: August 2003

Our feathered friends might be hiding a few antiaging tricks under their wings: New results suggest that long-lived birds withstand damage caused by reactive oxygen molecules better than either mammals or short-lived birds do.

Pound for pound, birds survive much longer than do mammals, but they also break down food for energy at higher rates. Those observations seem paradoxical because metabolic activity produces reactive oxygen species (ROS)--destructive molecules that likely contribute to aging (see
"The Two Faces of Oxygen"
). Recent studies indicate, however, that compared to mammals, long-lived birds produce fewer ROS per molecule of oxygen processed. And those birds also appear more adept at preventing ROS from causing cellular damage. But no one had established whether all birds or only long-lived ones carry these traits.

To investigate this issue, Ogburn and colleagues cultured cells from two species of birds: quail, which live about 4 years, and budgerigars (common pets fondly known as budgies), whose longevity can top 20 years. They also tested short- and long-lived mammals: mice, with a life-span of 3 years, and humans, who can survive to ages greater than 100. The researchers subjected the cell cultures to oxidative stress by exposing them to high concentrations of oxygen or hydrogen peroxide, and then they counted the cells that persisted. A higher percentage of budgie cells survived the assault than did those from the other three species. Additional experiments indicate that the budgies' superior defenses require active genes: When the researchers added chemical inhibitors of either messenger RNA or protein synthesis to the cells, budgie cell survival after treatment dropped to the level measured in the other three species. The results indicate that long-lived birds fend off oxidative damage better than do their less-robust cousins.
It's unclear if the cell culture model accurately reflects the response of cells in vivo. But the system does give scientists a controlled way to compare species and flush out budgies' possible secrets to a longer life. Budgies could boast a greater quantity of the same antioxidant enzymes that shorter-lived species employ, or they might have developed unique strategies for dealing with oxidative injury. Pinpointing the genes responsible for the difference between species might reveal the answer. Such information could enhance our understanding of possible connections between oxidative damage and aging and hint at ways to give wings to our own defenses.
--R. John Davenport

C. E. Ogburn, K. Carlberg, M. A. Ottinger, D. J. Holmes, G. M. Martin, S. N. Austad, Exceptional Cellular Resistance to Oxidative Damage in Long-Lived Birds Requires Active Gene Expression.
J. Gerontol. A Biol. Sci. Med. Sci.
56
, B468-B474 (2001).
[Abstract]
[Full Text]
They're Alive! Protein potion brings senescent cells back from the (un)dead
Authors: Davenport R. John 
Published: August 2003

Like zombies, senescent cells join the ranks of the undead. They no longer divide, but they don't die either. Now it turns out that these cellular freaks possess the resources for resurrection to a more vigorous existence: The right brew of normal proteins can kick-start DNA replication in the stalled cells.
Until now, scientists needed deviant proteins to shock senescent cells back to life: Cancer-causing molecules activate two cellular pathways that stimulate division. In the new work, Sarraj and colleagues mixed and matched benign proteins, looking for a combination that spurs senescent cells to start reproducing again. They tested Mdm2, which distracts the p53 protein from one of its usual jobs: inhibiting cell proliferation. Other candidates were three E2F proteins, which boost the production of molecules that encourage cells to multiply. Because senescent cells contain more p53 and less E2F than do normal cells, the researchers reasoned that providing additional Mdm2 or E2F might trigger cell duplication. To test this idea, they infected senescent human fibroblasts--cells that compose connective tissue--with various combinations of viruses, each of which is engineered to produce one of these proteins. By looking for incorporation of a tagged molecule into DNA, they were able to determine what fraction of cells copied their DNA--an indication that cell division had started up again. Serving up extra Mdm2 or E2F individually had a modest effect: 10% to 30% of the cells showed signs of replicative life. But Mdm2 plus any one of the three E2Fs jolted 50% to 70% of the cells back into action.

Scientists have suspected that the right blend of cellular proteins could recharge senescent cells, but they hadn't shown that experimentally until now. The results provide evidence that supplying certain proteins lacking in senescent cells can indeed reverse the process. The study enhances our knowledge about possible links between senescence and cancer or aging. In animals, senescence might fight cancer by stunting the growth of damaged cells before they start dividing unchecked (see
"Dangerous Liaisons"
). And accumulation of senescent cells might be to blame for some of the effects of aging (see
"More Than a Sum of Our Cells"
). But no one's likely to start receiving antiaging E2F/Mdm2 injections any time soon: The treated cells might retain the harmful characteristics that sparked senescence in the first place and rejuvenating them might just produce more of a bad thing. But knowing how to bring senescent cells back to life will undoubtedly shed light on the spell that makes them zombies in the first place.

--R. John Davenport; suggested by Chang-Su Lim

S. Sarraj, R. Farb, R. Martell, Reconstitution of DNA synthetic capacity in senescent normal human fibroblasts by expressing cellular factors E2F and Mdm2.
Exp. Cell Res.
270
, 268-276 (2001).
[Abstract]
[PDF]
Ebb Tide: Brain center linked to decrease in egg-producing waves
Authors: Davenport R. John 
Published: August 2003

As mammals age, one of the first things to go is reproductive capacity. Ovulation becomes irregular, because waves of luteinizing hormone (LH) don't crest as high as before. New results indicate that a reduction in nerve impulses from a particular part of the brain is partly responsible for lowering the levels of the hormone that triggers LH production.
Release of luteinizing hormone-releasing hormone (LH-RH) from neurons in the hypothalamus, a part of the brain that governs a host of hormone-controlled bodily functions, spurs the pituitary gland to produce waves of LH. These so-called LH surges stimulate egg release from the ovaries, but they diminish during aging because production of LH-RH by hypothalamic neurons decreases. Exactly what causes this decline is unknown, but some suspect that neurons from elsewhere in the hypothalamus might be to blame. Previous work implicated a region known as the AVPv: AVPv nerve cells connect to LH-RH-producing neurons, and damaging the AVPv blocks LH surges. But it hasn't been clear if a decrease in AVPv activity with advancing years prevents LH-RH synthesis.
In search of a missing link, Le and colleagues looked for activity in AVPv and LH-RH neurons in the brains of young and middle-aged rats sacrificed in the midst of an LH surge. The team used antibodies to detect the presence of the Fos protein, an indicator of neuron activity. A smaller percentage of LH-RH neurons in middle-aged rat brains contained Fos as compared with young rat brains. In addition, a similarly reduced fraction of neurons in the AVPv region of middle-aged brains lit up with Fos. The researchers then damaged AVPv in young rats and monitored LH-RH neuron activity. LH-RH neurons on the same side of the brain as the lesion took a hit, expressing no Fos; LH-RH neurons on the uninjured side of the brain carried on normally. The results add to evidence that nerves in the AVPv stimulate LH-RH production. They also suggest that reduced AVPv firing accounts in part for the waning LH-RH production--and, in turn, the declining LH and loss of ovulation--that comes with age.
Why AVPv activity falls over time is unclear, and the answer is not likely to be simple. The AVPv takes in signals from multiple hormones and neurons, so the change probably involves more than one trigger. And other brain centers could play roles as well. Further elucidating this pathway will help researchers understand how once-swelling hormonal seas flatten.
--R. John Davenport

W.-W. Le, P. M. Wise, A. Z. Murphy, L. M. Coolen, G. E. Hoffman, Parallel declines in Fos activation of the medial anteroventral periventricular nucleus and LHRH neurons in middle-aged rats.
Endocrinology
142
, 4976-4982 (2001).
[Abstract]
[Full Text]