Critical pathway in cell cycle may lead to cancer development

July 11, 2013, Salk Institute
From left are Salk scientists Makoto Hayashi, Anthony Cesare and Jan Karlseder. Credit: Salk Institute for Biological Studies

A team of scientists at the Salk Institute for Biological Studies has identified why disruption of a vital pathway in cell cycle control leads to the proliferation of cancer cells. Their findings on telomeres, the stretches of DNA at the ends of chromosomes that protect our genetic code and make it possible for cells to divide, suggest a potential target for preventive measures against cancer, aging and other diseases. The findings were published July 11 in Molecular Cell.

Telomeres have been compared to the plastic tips at the end of shoelaces because they prevent the ends of from fraying and sticking to each other, which scrambles the and may promote cancer. They are crucial to DNA replication, and aging. Each time a human cell divides, its telomeres become shorter. When they become too short, the cell can no longer divide and becomes inactive, or "senescent," or dies. Cells can escape this fate by activating an enzyme called , which prevents telomeres from getting shorter and allows the cells to continue to grow and divide. Uncontrolled cellular growth is a primary hallmark of , and shortened telomeres have been identified in pancreatic, bone, prostate, bladder, lung, kidney and head and neck cancers.

"As telomeres shorten during normal [cellular] aging, they activate a DNA damage response to arrest cell growth, which protects our DNA from harm," says senior study author Jan Karlseder, a professor in Salk's Molecular and Cell Biology Laboratory and holder of the Donald and Darlene Shiley Chair.

Karlseder and his team identified that cell growth arrest due to shortening telomeres is confined to one specific portion of the cell cycle, called the G1 phase, which is the most protected stage of the cell cycle. "The pathway controlling G1-phase growth arrest, however, is commonly altered in cancer cells, allowing cancer cells to divide despite shortened telomeres, which can lead to the genomic instability seen in malignant cells."

In the study, Karlseder and his colleagues mimicked the process of cellular aging by partially removing a protein called TRF2 from the telomeres of human fibrosarcoma (a type of cancer that affects connective tissue) cells. By doing so, they were able to experimentally reproduce the process that occurs naturally as cells age. This telomere "deprotection" exposed the ends of chromosomes during certain stages of the cell cycle. In this state, they found that telomeres exhibited a partial DNA damage response: the ends of chromosomes were protected against fusing and fraying, but cell growth was still arrested.

"Basically," says lead author Anthony Cesare, a research associate in Karlseder's laboratory, "there's cell growth arrest without genomic instability. Thus, telomere aging, in normal, healthy cells and living organisms, means cell arrest, but no harmful genetic effects."

The Salk scientists identified the p53 pathway, a molecular mechanism that normally protects a cell's genetic material and suppresses tumors, as the key player in the response to telomere deprotection. When cells lose the function of p53, the gene at the center of the pathway, they can no longer arrest cells in the G1 phase, an important point in the cell cycle for repairing DNA damage or, if the damage cannot be repaired, targeting the cell for programmed death. Most commonly, p53 is lost in cancer cells due to a mutation in the p53 gene or the inactivation of p53 protein function through infection from cancer-causing viruses.

Because telomere deprotection results in a partial DNA damage response that only arrests cells in G1 through the p53 pathway, once cells lose p53 function telomere deprotection no longer arrests growth. "Cells without functional p53 are able to divide with deprotected telomeres, which causes genomic instability, a common feature of malignant cells," says Karlseder.

Karlseder and his colleagues believe that better understanding the telomere shortening process may lead to the ability to influence and, as a result, stunt cancer cell growth. They say the next step is determining why this deprotection response is muted in cancer cells, and possibly affecting this process to prevent cancer cells from growing.

Explore further: Telomere length influences cancer cell differentiation

Related Stories

Telomere length influences cancer cell differentiation

June 27, 2013
Researchers from the Japanese Foundation for Cancer Research in Tokyo have discovered that forced elongation of telomeres (extensions on the end of chromosomes) promotes the differentiation of cancer cells, probably reducing ...

Sending out an SOS: How telomeres incriminate cells that can't divide

March 12, 2012
The well-being of living cells requires specialized squads of proteins that maintain order. Degraders chew up worn-out proteins, recyclers wrap up damaged organelles, and-most importantly-DNA repair crews restitch anything ...

Abnormalities in new molecular pathway may increase breast cancer risk

June 17, 2013
A new molecular pathway involving the gene ZNF365 has been identified and abnormalities in that pathway may predict worse outcomes for patients with breast cancer, according to data published in Cancer Discovery, a journal ...

Researchers identify new potential target for cancer therapy

April 19, 2013
Researchers at UT Southwestern Medical Center have found that alternative splicing – a process that allows a single gene to code for multiple proteins – appears to be a new potential target for anti-telomerase cancer ...

Wip1 could be new target for cancer treatment

May 6, 2013
Researchers have uncovered mutations in the phosphatase Wip1 that enable cancer cells to foil the tumor suppressor p53, according to a study in The Journal of Cell Biology. The results could provide a new target for the treatment ...

Recommended for you

How cancer metastasis happens: Researchers reveal a key mechanism

January 18, 2018
Cancer metastasis, the migration of cells from a primary tumor to form distant tumors in the body, can be triggered by a chronic leakage of DNA within tumor cells, according to a team led by Weill Cornell Medicine and Memorial ...

Modular gene enhancer promotes leukemia and regulates effectiveness of chemotherapy

January 18, 2018
Every day, billions of new blood cells are generated in the bone marrow. The gene Myc is known to play an important role in this process, and is also known to play a role in cancer. Scientists from the German Cancer Research ...

These foods may up your odds for colon cancer

January 18, 2018
(HealthDay)—Chowing down on red meat, white bread and sugar-laden drinks might increase your long-term risk of colon cancer, a new study suggests.

The pill lowers ovarian cancer risk, even for smokers

January 18, 2018
(HealthDay)—It's known that use of the birth control pill is tied to lower odds for ovarian cancer, but new research shows the benefit extends to smokers or women who are obese.

Researchers develop swallowable test to detect pre-cancerous Barrett's esophagus

January 17, 2018
Investigators at Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center have developed a simple, swallowable test for early detection of Barrett's esophagus that offers promise ...

Scientists zoom in to watch DNA code being read

January 17, 2018
Scientists have unveiled incredible images of how the DNA code is read and interpreted—revealing new detail about one of the fundamental processes of life.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.