August 17, 2017 Human chromosomes (grey) capped by telomeres (white). Credit: PD-NASA; PD-USGOV-NASA
A mutation that helps make cells immortal is critical to the development of a tumor, but new research at the University of California, Berkeley suggests that becoming immortal is a more complicated process than originally thought.
The key to immortalization is an enzyme called telomerase, which keeps chromosomes healthy in cells that divide frequently. The enzyme lengthens the caps, or telomeres, on the ends of chromosomes, which wear off during each cell division.
When the telomeres get too short, the ends stick to one another, wreaking havoc when the cell divides and in most cases killing the cell. The discovery of telomerase and its role in replenishing the caps on the ends of the chromosomes, made by Elizabeth Blackburn and Carol Greider at UC Berkeley and John Szostak at Harvard University in the 1980s, earned them a Nobel Prize in Physiology or Medicine in 2009.
Because telomeres get shorter as cells age, scientists theorized that cancer cells - which never age - become immortalized by turning on production of telomerase in cells that normally don't produce it, allowing these cells to keep their long telomeres indefinitely. An estimated 90 percent of all malignant tumors use telomerase to achieve immortality, and various proposed cancer therapies focus on turning down the production of telomerase in tumors.
The new research, which studied the immortalization process using genome-engineered cells in culture and also tracked skin cells as they progressed from a mole into a malignant melanoma, suggests that telomerase plays a more complex role in cancer.
"Our findings have implications for how to think about the earliest processes that drive cancer and telomerase as a therapeutic target. It also means that the role of telomere biology at a very early step of cancer development is vastly underappreciated," said senior author Dirk Hockemeyer, a UC Berkeley assistant professor of molecular and cell biology. "It is very likely that what we find in melanoma is true for other cancer types as well, which would warrant that people look more carefully at the role of early telomere shortening as a tumor suppressing mechanism for cancer."
The results will be reported online August 17 as a "first release" publication from the journal Science.
From nevus to cancer
Hockemeyer and his UC Berkeley colleagues, in collaboration with dermatopathologistBoris Bastian and his colleagues at UCSF, found that immortalization is a two-step process, driven initially by a mutation that turns telomerase on, but at a very low level. That mutation is in a promoter, a region upstream of the telomerase gene - referred to as TERT - that regulates how much telomerase is produced. Four years ago, researchers reported that some 70 percent of malignant melanomas have this identical mutation in the TERT promoter.
The TERT promoter mutation does not generate enough telomerase to immortalize the pre-cancerous cells, but does delay normal cellular aging, Hockemeyer said, allowing more time for additional changes that turns telomerase up. He suspects that the telomerase levels are sufficient to lengthen the shortest telomeres, but not keep them all long and healthy.
If cells fail to turn up telomerase, they also fail to immortalize, and eventually die from short telomeres because chromosomes stick together and then shatter when the cell divides. Cells with the TERT promoter mutation are more likely to up-regulate telomerase, which allows them to continue to grow despite very short telomeres.
Yet, Hockemeyer says, telomerase levels are marginal, resulting is some unprotected chromosome ends in the surviving mutant cells, which could cause mutations and further fuel tumor formation.
"Before our paper, people could have assumed that the acquisition of just this one mutation in the TERT promoter was sufficient to immortalize a cell; that any time when that happens, the telomere shortening is taken out of the equation," Hockemeyer said. "We are showing that the TERT promoter mutation is not immediately sufficient to stop telomeres from shortening."
It is still unclear, however, what causes the eventual up-regulation of telomerase that immortalizes the cell. Hockemeyer says that it's unlikely to be another mutation, but rather an epigenetic change that affects expression of the telomerase gene, or a change in the expression of a transcription factor or other regulatory proteins that binds to the promoter upstream of the telomerase gene.
"Nevertheless, we have evidence that the second step has to happen, and that the second step is initiated by or is occurring at a time where telomeres are critically short and when telomeres can be dysfunctional and drive genomic instability," he said.
In retrospect, not a surprise
Though most cancers seem to require telomerase to become immortal, only some 10 to 20 percent of cancers are known to have a single-nucleotide change in the promoter upstream of the telomerase gene. However, these include about 70 percent of all melanomas and 50 percent of all liver and bladder cancers.
Hockemeyer said that the evidence supporting the theory that the TERT promoter mutation up-regulated telomerase has always been conflicting: cancer cells tend to have chromosomes with short telomeres, yet have higher levels of telomerase, which should produce longer telomeres.
According to the new theory, the telomeres are short in precancerous cells because telomerase is turned on just enough to maintain but not lengthen the telomeres.
"Our paper reconciles contradictory information about the cancers that carry these mutations," Hockemeyer said.
The finding also resolves another recent counterintuitive finding: that people with shorter telomeres are more resistant to melanoma. The reason, he said, is that if a TERT promoter mutation arises to push a precancerous lesion - the mole or nevus - toward a melanoma, the chances are greater in someone with short telomeres that the cell will die before it up-regulates telomerase and immortalizes the cells.
The study also involved engineering TERT promoter mutations in cells differentiated from human pluripotent stem cells and following their progression toward cellular immortality. The results were identical to the progression seen in human skin lesions obtained from patients in UCSF's Helen Diller Family Comprehensive Cancer Center and examined in the Clinical Cancer Genomics Laboratory, which Bastian directs.
Explore further: Unraveling the mystery of why cancer cells survive and thrive
More information: K. Chiba el al., "Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism," Science (2017). science.sciencemag.org/lookup/ 1126/science.aao0535
Scientists at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg have gained important insights for stem cell research which are also applicable to human tumours and could lead to the development of new ...
Please sign in to add a comment. Registration is free, and takes less than a minute. Read more
Continue reading here:
Two-step process leads to cell immortalization and cancer - Medical Xpress
- Here's What You Should Know About Stem Cell Beauty Products - Who What Wear - October 29th, 2023 [October 29th, 2023]
- After Death Dangles Answers to the Only Important Question - The Stream - October 29th, 2023 [October 29th, 2023]
- Igniting Hope conference aims to end race-based health disparities ... - University at Buffalo - October 29th, 2023 [October 29th, 2023]
- 10 Best Horror Anime on Crunchyroll - Screen Rant - October 29th, 2023 [October 29th, 2023]
- 10 Flowers That Represent Freedom - AZ Animals - October 29th, 2023 [October 29th, 2023]
- Demon Slayer: What is Muzan's illness? Explained - Sportskeeda - October 29th, 2023 [October 29th, 2023]
- Enterprise's Archer Copied Picard's Star Trek: Insurrection Romance - Screen Rant - October 29th, 2023 [October 29th, 2023]
- Anemone Flowers: Meaning, Symbolism, and Proper Occasions - AZ Animals - October 29th, 2023 [October 29th, 2023]
- The billion-dollar search for immortality - UnHerd - June 24th, 2023 [June 24th, 2023]
- Should Medicine Still Bother With Eponyms? - The New York Times - June 24th, 2023 [June 24th, 2023]
- Immortality: A Love Story - Plugged In - June 24th, 2023 [June 24th, 2023]
- Harvard morgue scandal: The history of selling body parts - The Boston Globe - June 24th, 2023 [June 24th, 2023]
- Imbibe yoga in its true spirit on the International Yoga Day - Daily Pioneer - June 24th, 2023 [June 24th, 2023]
- Everything you need to know about Nick Fury as Secret Invasion arrives - Yahoo Entertainment - June 24th, 2023 [June 24th, 2023]
- Some Interesting Facts On The Hindu Epic Ramayana - The Movie Blog - June 24th, 2023 [June 24th, 2023]
- Will AI Become Our New Gods? - Answers In Genesis - June 24th, 2023 [June 24th, 2023]
- There's food growing in The Woodlands. Here's how to forage for it ... - Houston Chronicle - June 24th, 2023 [June 24th, 2023]
- One Piece: Op-Op Fruit is the source of Imus immortality - Dexerto - June 24th, 2023 [June 24th, 2023]
- King Charles III's Coronation at the Convergence of Policy ... - JURIST - May 12th, 2023 [May 12th, 2023]
- Ancient Greek healing temple in Trikala to be restored - The Greek Herald - May 12th, 2023 [May 12th, 2023]
- The long and short of telomere rejuvenation | Opinion - Chemistry World - May 12th, 2023 [May 12th, 2023]
- Is there a solution to the puzzle that is cancer? The fundamental ... - Sciencenorway - May 12th, 2023 [May 12th, 2023]
- The Week In Russia: Theater Of War - Radio Free Europe / Radio Liberty - May 12th, 2023 [May 12th, 2023]
- No. 788: Hi, Mom were getting ready for your big day with dirty ... - Innovate Long Island - May 12th, 2023 [May 12th, 2023]
- Star Trek: Who Is The Oldest Human? - GameRant - May 12th, 2023 [May 12th, 2023]
- Sabbaticals: A Gateway to Reimagining Health - Non Profit News - Nonprofit Quarterly - May 12th, 2023 [May 12th, 2023]
- Florence Nightingale birth anniversary: The Lady with the Lamp who founded modern nursing during Crimean War - News9 LIVE - May 12th, 2023 [May 12th, 2023]
- Defence Secretary oral statement on war in Ukraine - GOV.UK - May 12th, 2023 [May 12th, 2023]
- TOM UTLEY: Mrs U and I are better prepared for the end. But scientists say we might live to 122! - Daily Mail - March 31st, 2023 [March 31st, 2023]
- Eddie Jones reveals NRL legend Andrew Johns was on the verge of a shock code switch in 2005 - Daily Mail - February 18th, 2023 [February 18th, 2023]
- The debauched world of Ozzy Osbourne - biting bats to Sharon finding him in bed with the nanny - Daily Mail - February 5th, 2023 [February 5th, 2023]
- 6 Benefits of Reishi Mushroom (Plus Side Effects and Dosage) - Healthline - December 23rd, 2022 [December 23rd, 2022]
- Alchemy - Wikipedia - December 23rd, 2022 [December 23rd, 2022]
- Emily Dickinson - Poems, Quotes & Death - Biography - December 23rd, 2022 [December 23rd, 2022]
- Alexis Carrel - Wikipedia - December 21st, 2022 [December 21st, 2022]
- Medicine MBChB - University Of Worcester - November 23rd, 2022 [November 23rd, 2022]
- Republic of Florence - Wikipedia - November 23rd, 2022 [November 23rd, 2022]
- Taoist sexual practices - Wikipedia - November 23rd, 2022 [November 23rd, 2022]
- Herbal medicine - Wikipedia - October 23rd, 2022 [October 23rd, 2022]
- Aubrey de Grey - Wikipedia - October 23rd, 2022 [October 23rd, 2022]
- Greek language - Wikipedia - October 23rd, 2022 [October 23rd, 2022]
- Gynostemma pentaphyllum - Wikipedia - October 23rd, 2022 [October 23rd, 2022]
- Lingzhi (mushroom) - Wikipedia - October 23rd, 2022 [October 23rd, 2022]
- The Hayflick Limit: Why Every Human Can Live Up to 125 Years - History of Yesterday - October 6th, 2022 [October 6th, 2022]
- Downtown Lecture Series, now in 10th year, will focus on sexualities - University of Arizona News - October 6th, 2022 [October 6th, 2022]
- Scent of Wind Review: A Simple Tale of Kindness From Iran Echoes the Countrys Masters - Yahoo Entertainment - October 6th, 2022 [October 6th, 2022]
- Proxy voting rises when Congress usually flies in and out of town, analysis finds - Oil City Derrick - October 6th, 2022 [October 6th, 2022]
- Keith Simpson reviews 'Boris Johnson: The Rise and Fall of a Troublemaker at Number 10' - PoliticsHome - October 6th, 2022 [October 6th, 2022]
- Disney+ Releases Official Trailer for the Original Series Limitless with Chris Hemsworth from National Geographic - Yahoo Finance - October 6th, 2022 [October 6th, 2022]
- True Fathers Resist the Holy Father - OnePeterFive - October 6th, 2022 [October 6th, 2022]
- Targeted-sequence of normal urothelium and tumor of patients with non-muscle invasive bladder cancer | Scientific Reports - Nature.com - October 6th, 2022 [October 6th, 2022]
- Cheers and Jeers: Thursday - Daily Kos - October 6th, 2022 [October 6th, 2022]
- North Korea tells officials that 350,000 people died of diseases this year - Radio Free Asia - October 6th, 2022 [October 6th, 2022]
- New York: World War II: Inventive Report An interactive presentation of how, without real danger, the - Game News 24 - October 6th, 2022 [October 6th, 2022]
- Soma (drink) - Wikipedia - October 2nd, 2022 [October 2nd, 2022]
- Lavish Qin Shi Huang Tomb Built for Immortality - October 2nd, 2022 [October 2nd, 2022]
- The Four Directions & Medicine Wheel of Native Americans - Gaia - October 2nd, 2022 [October 2nd, 2022]
- Kanye, Selena Gomez have bipolar disorder. Why is there a stigma? - USA TODAY - October 2nd, 2022 [October 2nd, 2022]
- Forrest Bess Was a Fisherman by Day and Painter of Wild Visions by Night. A New Show Explores His Legacy - artnet News - October 2nd, 2022 [October 2nd, 2022]
- 'Star Wars': 9 Force Powers Used Only by The Jedi - We Got This Covered - October 2nd, 2022 [October 2nd, 2022]
- The CIA has invested in wooly mammoth resurrection technology and nobody knows why - Daily Star - October 2nd, 2022 [October 2nd, 2022]
- Here's why we age - Hindustan Times - September 20th, 2022 [September 20th, 2022]
- Blind mystic Baba Vanga's five predictions for 2023 - from end of births to nuclear disaster - Irish Mirror - September 20th, 2022 [September 20th, 2022]
- President Biden Says Covid-19 Pandemic is Over in the US - Slashdot - September 20th, 2022 [September 20th, 2022]
- Immortality a possibility? This jellyfish could have the answer - Ohmymag - September 17th, 2022 [September 17th, 2022]
- Early Puberty Resulting From Excessive Smartphone Screen Time? Here's What This Study Found - Forbes - September 17th, 2022 [September 17th, 2022]
- Godard's assisted suicide - not an option everywhere - SWI swissinfo.ch - SWI swissinfo.ch in English - September 17th, 2022 [September 17th, 2022]
- Akudaaya: Tinubu, Abacha and Shettima's Theory of Ruthless Leadership -By Festus Adedayo - Opinion Nigeria - September 17th, 2022 [September 17th, 2022]
- On The Lord Of The Rings: The Rings Of Power, a hard rains a-gonna fall - The A.V. Club - September 17th, 2022 [September 17th, 2022]
- The longevity diet: Lots of beans and periodic fasts slow ageing - The New Daily - September 17th, 2022 [September 17th, 2022]
- The Real Effects Aloe Vera Has On Your Body - Health Digest - September 11th, 2022 [September 11th, 2022]
- Its Time To Rethink the Origins of Pain - Scientific American - September 11th, 2022 [September 11th, 2022]
- Queen Elizabeth II: Celebrities send well-wishes as world waits for update on health - The Independent - September 11th, 2022 [September 11th, 2022]
- The Moon: Earths Eighth Continent to This Jellyfish is Immortal (Planet Earth Report) - The Daily Galaxy --Great Discoveries Channel - September 11th, 2022 [September 11th, 2022]
- This president was shot in the back, but the doctors are the ones who killed him - Salon - September 11th, 2022 [September 11th, 2022]
- As The Royal Family Deals With Devastating Racism Accusations From Meghan Markle, 96-Year-Old Queen Elizabeth II Now Under Extensive Medical Care as... - September 11th, 2022 [September 11th, 2022]
- To quit or not to quit: The hardest question for sporting greats - Deccan Herald - September 11th, 2022 [September 11th, 2022]
- OND: Harvest moon, climate refugees, wall wind turbine, JWST and more - Daily Kos - September 11th, 2022 [September 11th, 2022]
- 10 Fantasy Shows Like Lord Of The Rings: The Rings Of Power You Should Check Out - /Film - September 11th, 2022 [September 11th, 2022]
- Jared Kushner is keeping fit because he thinks he might live forever - Business Insider - August 27th, 2022 [August 27th, 2022]