Unexpected regulation of transcription factors critical to developmentOctober 10, 2017
AMHERST, Mass. - A team of developmental biologists at the University of Massachusetts Amherst led by Dominique Alfandari, with others at MIT, report in a new paper that they have for the first time described how two transcription factors that are "absolutely essential for human development" are regulated by a cell surface metalloprotease known as ADAM13. The discovery adds to knowledge of how cells migrate in vertebrate embryos, how stem cells differentiate and how cancer cells metastasize.
ADAM13 belongs to a group of proteins called proteases that cut other proteins to change their function. Alfandari says, "Five years ago we discovered that ADAM metalloproteases control gene expression in a cell; no one had done that before. In this new paper, we describe the details of the mechanism by which the ADAM13 protein on the cell surface can affect gene expression in the nucleus, which is remarkable."
"We found that ADAM13 has to work with a series of other proteins and two transcription factors, tfap2- and arid3a. We've described every step they take and how they are changed to get the work done. Arid3a shuttles between ADAM13 on the surface and genes in the nucleus. We've seen that some ADAMs can do this but, for example, ADAM9 can't do it at all," the molecular biologist adds. Details appear now in the online, open-access journal eLIFE.
In studies supported by the NIH's National Institute of Dental and Craniofacial Research, Alfandari and colleagues including co-investigator Helene Cousin and first author and postdoctoral researcher Vikram Khedgikar, are well known for tracking individual cells in frog embryos to learn how the ADAM13 protease controls proteins in the cranial neural crest to form the jaw and face. Cranial neural crest cell migration is common to all vertebrate embryos including humans, and defects in their production or migration lead to severe facial malformations.
After many years of this work, Alfandari and colleagues are now getting more into the detail of what the ADAM family of proteins can do, he notes. "What is exciting about that is we've shown that ADAM13, which is one of more than 30 members of this family, controls two essential transcription factors that bind to DNA to turn on genes."
He explains that arid3a in humans controls cell-fate decisions, that is, it directs uncommitted stem cells to differentiate from a naïve state to a cell that knows its job. In this role, arid3a can be thought of as an "anti-stem-cell factor," because it shuts down the stem cell's ability to remain naïve. Alfandari quips, "It kicks the kids out of home and forces them to go to school and learn a trade."
A special role of arid3a in forcing the cell to specialize has implications for cancer, he adds. When cells differentiate they often stop dividing; they rarely do both. By forcing differentiation, arid3a suppresses cell division. He explains, "In a tumor, this means arid3a forces tumor cells to stay in place and perform work rather than dividing. They are more benign, tending to stay in place and not metastasize." Thus, the prognosis for a patient with a tumor that has a lot of arid3a in it is better than one that has little arid3a, because with less, they proliferate more.
Alfandari adds, "Perhaps it may give us a new tool to control tumors, if you can control ADAM activity from outside of the cell, you could control arid3a as well. This is long-term, I'm dreaming of what could happen. We don't know yet if ADAM can play a role in this way to control cancer, but it is a new possibility."
As for tfap2-, in all species studied so far it controls the cells at the border of the neural plate in the embryo, which go on to form all of the sensory organs for hearing, vision and smell, plus all the cranio-facial structures, so "tfap2- pretty much defines this group of cells during vertebrate evolution," the lab director points out.
"For our work this is very important because it helps us understand how neural crest cells acquire their specialization and learn how and where to move. It also suggests that ADAM proteins in other kinds of cells may regulate similar processes."
The molecular biologist says that ADAM13 has been thought of as "a low-key player, it was not thought to be critical." Indeed, he thinks of ADAM proteins as a fine-tuning mechanism, like the coach on the sidelines of a football game. "If you lose the coach, the team can continue to function even if less efficient. If an embryo is missing ADAM13, it can survive, but with birth defects."
However, the transcription factors arid3a and tfap2- are far more important, more akin to a quarterback. "If you lose the quarterback, the team can't go on," he says. "If you lost arid3a and tfap2-alpha, these are absolutely critical for the embryo and without them it cannot survive."
In the future, Alfandari says, his lab will continue to define the parts of ADAM13 and arid3a that communicate with each other and how arid3a shuttles between ADAM on the cell surface and genes in the nucleus. "Our goal is to figure out the specific protein sequences that control arid3a," he notes. "That will take another five years."
University of Massachusetts at Amherst
Related Cancer Articles:
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Is investment in research to develop new treatments the best approach to controlling cancer?
The University of Illinois Cancer Center and Governors State University have received a joint four-year, $1.5 million grant from the National Cancer Institute to help both institutions conduct community-based research to reduce cancer-related health disparities in Chicago's south suburbs.
The Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research will join forces to sponsor the first International Cancer Immunotherapy Conference at the Sheraton New York Times Square Hotel in New York, Sept.
Related Cancer Reading:
The Cancer-Fighting Kitchen, Second Edition: Nourishing, Big-Flavor Recipes for Cancer Treatment and Recovery
by Rebecca Katz (Author), Mat Edelson (Author)
This new and revised edition of the IACP award-winning cookbook brings the healing power of delicious, nutritious foods to those whose hearts and bodies crave a revitalizing meal, through 150 new and updated recipes.
Featuring science-based, nutrient-rich recipes that are easy to prepare and designed to give patients a much-needed boost by stimulating appetite and addressing treatment side effects including fatigue, nausea, dehydration, mouth and throat soreness, tastebud changes, and weight loss. A step-by-step guide helps patients nutritionally prepare for all phases of... View Details
F*ck Cancer: A totally inappropriate self-affirming adult coloring book (Totally Inappropriate Series) (Volume 4)
by Jen Meyers (Author)
*A portion of the proceeds from this book will be donated to support research dedicated to finding a cure for cancer. Because fuck cancer.
This book is for you.
If you are fighting cancer, this is for you. If your brother, sister, mom, dad, son, daughter, relative, or friend is fighting cancer, this is for you. If you've lost someone to cancer like I have, this is for you. If cancer affects your life in any way, this is for you.
The stress of cancer can feel crushing. But perhaps this book can help you get away from it all, if only for a little... View Details
The Truth about Cancer: What You Need to Know about Cancer's History, Treatment, and Prevention
by Ty M Bollinger (Author)
Cancer touches more lives than you may think. According to the World Health Organization, one out of three women alive today, and one out of two men, will face a cancer diagnosis in their lifetime.
To Ty Bollinger, this isn’t just a statistic. It’s personal. After losing seven members of his family to cancer over the course of a decade, Ty set out on a global quest to learn as much as he possibly could about cancer treatments and the medical industry that surrounds the disease. He has written this book to share what he’s uncovered—some of which may shock you—and to give you... View Details
The Cancer Revolution: A Groundbreaking Program to Reverse and Prevent Cancer
by Leigh Erin Connealy (Author)
When it comes to cancer, conventional doctors are trained to treat their patients exclusively with surgery, radiation, and chemotherapy. These methods are grueling on the whole body - and they don't treat beyond the tumor or the cancer itself. The focus is on the disease, not the whole person - and because of this, the outcomes in conventional medicine can be bleak.
But it doesn't have to be this way. Dr. Leigh Erin Connealy has developed a whole-person approach to treating cancer - and these treatments have helped thousands of patients through her Cancer Center for Healing. In... View Details
Cancer: 50 Essential Things to Do: 2013 Edition
by Greg Anderson (Author)
The ground-breaking classic guide to surviving cancer?now completely updated!
Revised and updated for the first time since 1999, this invaluable guide to cancer recovery offers an easily accessible plan for patients and family members. Written by a cancer survivor, the book is an inspiring, action-oriented roadmap for those who choose to adopt a stance of hope and take charge of their diagnosis.
With penetrating insights that bring together more than two decades of scientifically supported research and experience, Anderson reveals a step-by-step holistic action plan... View Details
Cancer Hates Tea: A Unique Preventive and Transformative Lifestyle Change to Help Crush Cancer
by Maria Uspenski (Author), Dr. Mary L. Hardy (Foreword)
Drink Tea to Tell Cancer ‘Hit the Road’
Become a tea lover with a purpose and help your body defend itself against cancer. Learn to embrace tea in all its varieties― green, white, black, pu-erh, herbal and more―as both a mental and physical experience to protect your health. Discover the history, growing information and health implications of each variety, as well as uniquely delicious methods to boost your intake with serving suggestions, food pairings and recipes that highlight the benefits of tea.
After her own battle with cancer, Maria Uspenski extensively... View Details
Anticancer: A New Way of Life
by David Servan-Schreiber MD PhD (Author)
The revolutionary, New York Times bestselling guide to the powerful lifestyle changes that fight and prevent cancer—an integrative approach based on the latest scientific research
“A common-sense blueprint for healthy living.” —Chicago Tribune
“Resonating with cancer support communities and recommended nationwide.” —Los Angeles Times
“Life affirming . . . filled with practical advice.” —The Seattle Times
David Servan-Schreiber was a rising... View Details
Beating Cancer with Nutrition (Fourth Edition) Rev
by Patrick Quillin (Author)
There is good news in the "war on cancer". Optimal nutrition coupled with appropriate medical treatment can dramatically improve the quality and quantity of life and chances for a complete remission for most cancer patients. A well-nourished cancer patient can better manage the disease. Cancer is the number two cause of death in America and the developed nations of the world with one out of four dying from cancer and 38% of women and 43% of men projected to develop cancer over their lifetime. While the overall death rate from cancer has not appreciably declined since... View Details
The Metabolic Approach to Cancer: Integrating Deep Nutrition, the Ketogenic Diet, and Nontoxic Bio-Individualized Therapies
by Dr. Nasha Winters ND FABNO L.Ac Dipl.OM (Author), Jess Higgins Kelley MNT (Author), Kelly Turner (Foreword)
The Optimal Terrain Ten Protocol to Reboot Cellular Health
Since the beginning of the twentieth century, cancer rates have increased exponentially―now affecting almost 50 percent of the American population. Conventional treatment continues to rely on chemotherapy, surgery, and radiation to attack cancer cells. Yet research has repeatedly shown that 95 percent of cancer cases are directly linked to diet and lifestyle. The Metabolic Approach to Cancer is the book we have been waiting for―it offers an innovative, metabolic-focused nutrition protocol that... View Details
The Emperor of All Maladies: A Biography of Cancer
by Siddhartha Mukherjee (Author)
Winner of the Pulitzer Prize, and now a documentary from Ken Burns on PBS, The Emperor of All Maladies is a magnificent, profoundly humane “biography” of cancer—from its first documented appearances thousands of years ago through the epic battles in the twentieth century to cure, control, and conquer it to a radical new understanding of its essence.
Physician, researcher, and award-winning science writer, Siddhartha Mukherjee examines cancer with a cellular biologist’s precision, a historian’s perspective, and a biographer’s passion. The result is an astonishingly... View Details