Opposite effect: Protein widely known to fight tumors also boosts cancer growth

UC San Diego researchers found that the PUMA protein works inside the cell's mitochondria to switch energy production processes and stimulate cancer growth.

Search for a description of "p53" and it becomes clear that this human protein is widely known for its cancer-fighting benefits, leading to its renown as "the guardian of the genome."

Scientists at the University of California San Diego have published a new study challenging that description.

Studying the "wild type" version of p53 (WTp53), the form that exists broadly in nature, Jinchul Kim, Lili Yu, Xuemei Fu, Yang Xu and their colleagues found evidence that in certain cases, WTp53 instead plays a role in promoting tumors, rather than suppressing them. This finding explains an established paradox that, whereas p53 is mutated in more than 50 percent of all human cancers, it is not frequently mutated in certain human cancers, such as liver cancer.

In the January 31 issue of Cancer Cell, the scientists describe the culmination of more than four years of research on liver cancer that shows that WTp53 stimulates tumor growth by enhancing cancer metabolism. The key, according to the researchers, is a protein known as PUMA (the acronym for "p53 upregulated modulator of apoptosis"), which works inside mitochondria, the energy hub of cells. The researchers found that, at appropriate levels, PUMA disrupts normal function of mitochondria and causes a switch from oxidative phosphorylation, a process for efficient energy production in cells, to glycolysis, an alternative energy path that helps boost cancer metabolism.

"The widely accepted idea is that p53 suppresses cancer, but in our study we would argue against that," said Xu, a professor in the Division of Biological Sciences' Section of Molecular Biology. "In some cancers it would have the opposite effect by promoting cancer."

Xu indicates that p53 indeed halts the initiation of tumors by reducing the oxidative phosphorylation that produces genome toxins. However, once tumors are established, p53 may function to enhance tumor progression.

"It's actually the same function but playing exactly the opposite role in two different contexts," said Xu of the research findings, which were based on a mix of data from cell samples, mouse models and human patients.

Xu says the research provides a warning for cancer drug discovery. Drug therapies designed to enhance p53's function in cancer patients may be inadvertently causing an opposite effect.

"This role of WTp53 can resolve several long-lasting paradoxes in p53 biology and will be instrumental in the development of cancer therapy, especially in the context of the highly pursued strategies to eliminate human cancer by either activating WTp53 or restoring WTp53 function to p53 mutants in cancers," the authors note in the paper.

Coauthors of the paper include Wancheng Chen, Yanxia Xu, Meng Wu, Qingshuang Tang, Bingbing Feng and Lei Jiang of the Southern Medical University's Cancer Research Institute (China); and Dilyana Todorova, Jingjin He and Guihua Chen of the Eighth Affiliated Hospital at Sun Yat-sen University (China).

Mars rover Curiosity makes first gravity-measuring traverse on the Red Planet

In a selfie taken in mid-January 2019, Mars rover Curiosity prepares to enter a new, clay-mineral-rich unit on its traverse up Mount Sharp in Gale Crater. Mission scientists are anxious to see what a new gravity-measuring technique will reveal about the mountain and Gale Crater's history.

A clever use of non-science engineering data from NASA's Mars rover Curiosity has let a team of researchers, including an Arizona State University graduate student, measure the density of rock layers in 96-mile-wide Gale Crater.

The findings, to be published February 1, 2019, in the journal Science, show that the layers are more porous than scientists had suspected. The discovery also gives scientists a novel technique to use in the future as the rover continues its trek across the crater and up Mount Sharp, a three-mile-high mountain in its center.

"What we were able to do is measure the bulk density of the material in Gale Crater," says Travis Gabriel, a graduate student in ASU's School of Earth and Space Exploration. He worked on computing what the grain density should be for the rocks and ancient lakebed sediments the rover has been driving over.

"Working from the rocks' mineral abundances as determined by the Chemistry and Mineralogy instrument, we estimated a grain density of 2810 kilograms per cubic meter," he says. "However the bulk density that came out of our study is a lot less -- 1680 kilograms per cubic meter."

The much lower figure shows that the rocks have a reduced density most likely resulting from the rocks being more porous. This means the rocks have been compressed less than scientists have thought.

Like a Smartphone, but better

The engineering sensors used in the study were accelerometers and gyroscopes, much like those found in every smartphone. In a phone, these determine its orientation and motion. Curiosity's sensors do the same, but with much greater precision, helping engineers and mission controllers navigate the rover across the martian surface.

But while the rover is standing still, the accelerometers also measure the local force of gravity at that spot on Mars.

The team took the engineering data from the first five years of the mission -- Curiosity landed in 2012 -- and used it to measure the gravitational tug of Mars at more than 700 points along the rover's track. As Curiosity has been ascending Mount Sharp, the mountain began to tug on it, as well -- but not as much as scientists expected.

"The lower levels of Mount Sharp are surprisingly porous," says lead author Kevin Lewis of Johns Hopkins University. "We know the bottom layers of the mountain were buried over time. That compacts them, making them denser. But this finding suggests they weren't buried by as much material as we thought."

Making Mount Sharp

Planetary scientists have long debated the origin of Mount Sharp. Mars craters the size of Gale have central peaks raised by the shock of the impact that made the crater. This would account for part of the mound's height. But the upper layers of the mound appear to be made of wind-scoured sediments more easily eroded than rock.

Did these sediments once fill the entire bowl of Gale Crater? If so, they might have weighed heavily on the materials at the base, compacting them.

But the new findings suggest Mount Sharp's lower layers have been compacted by only a half-mile to a mile (1 to 2 kilometers) of material -- much less than if the crater had been completely filled.

"There are still many questions about how Mount Sharp developed, but this paper adds an important piece to the puzzle," said Ashwin Vasavada, Curiosity's project scientist at NASA's Jet Propulsion Laboratory in Pasadena, California, which manages the mission. "I'm thrilled that creative scientists and engineers are still finding innovative ways to make new scientific discoveries with the rover."

Gabriel adds, "This is a testament to the utility of having a diverse set of techniques with the Curiosity rover, and we're excited to see what the upper layers of Mount Sharp have in store."

Hubble fortuitously discovers a new galaxy in the cosmic neighborhood

This composite image shows the location of the accidentally discovered dwarf galaxy Bedin 1 behind the globular cluster NGC 6752. The lower image, depicting the complete cluster, is a ground-based observation from the Digitized Sky Survey 2. The upper right image shows the full field of view of the NASA/ESA Hubble Space Telescope. The upper left one highlights the part containing the galaxy Bedin 1.

Astronomers using the NASA/ESA Hubble Space Telescope to study some of the oldest and faintest stars in the globular cluster NGC 6752 have made an unexpected finding. They discovered a dwarf galaxy in our cosmic backyard, only 30 million light-years away. The finding is reported in the journal Monthly Notices of the Royal Astronomical Society: Letters.

An international team of astronomers recently used the NASA/ESA Hubble Space Telescope to study white dwarf stars within the globular cluster NGC 6752. The aim of their observations was to use these stars to measure the age of the globular cluster, but in the process they made an unexpected discovery.

In the outer fringes of the area observed with Hubble's Advanced Camera for Surveys a compact collection of stars was visible. After a careful analysis of their brightnesses and temperatures, the astronomers concluded that these stars did not belong to the cluster -- which is part of the Milky Way -- but rather they are millions of light-years more distant.

Our newly discovered cosmic neighbour, nicknamed Bedin 1 by the astronomers, is a modestly sized, elongated galaxy. It measures only around 3000 light-years at its greatest extent -- a fraction of the size of the Milky Way. Not only is it tiny, but it is also incredibly faint. These properties led astronomers to classify it as a dwarf spheroidal galaxy.

Dwarf spheroidal galaxies are defined by their small size, low-luminosity, lack of dust and old stellar populations [1]. 36 galaxies of this type are already known to exist in the Local Group of Galaxies, 22 of which are satellite galaxies of the Milky Way.

While dwarf spheroidal galaxies are not uncommon, Bedin 1 has some notable features. Not only is it one of just a few dwarf spheroidals that have a well established distance but it is also extremely isolated. It lies about 30 million light-years from the Milky Way and 2 million light-years from the nearest plausible large galaxy host, NGC 6744. This makes it possibly the most isolated small dwarf galaxy discovered to date.

From the properties of its stars, astronomers were able to infer that the galaxy is around 13 billion years old -- nearly as old as the Universe itself. Because of its isolation -- which resulted in hardly any interaction with other galaxies -- and its age, Bedin 1 is the astronomical equivalent of a living fossil from the early Universe.

The discovery of Bedin 1 was a truly serendipitous find. Very few Hubble images allow such faint objects to be seen, and they cover only a small area of the sky. Future telescopes with a large field of view, such as the WFIRST telescope, will have cameras covering a much larger area of the sky and may find many more of these galactic neighbours.

Notes

[1] While similar to dwarf elliptical galaxies in appearance and properties, dwarf spheroidal galaxies are in general approximately spherical in shape and have a lower luminosity.

More information

The Hubble Space Telescope is a project of international cooperation between ESA and NASA.

The results were presented in the letter The HST Large Programme on NGC 6752. I. Serendipitous discovery of a dwarf galaxy in background, published in the journal Monthly Notices of the Royal Astronomical Society: Letters.

The international team of astronomers that carried out this study consists of L. R. Bedin (INAF-Osservatorio Astronomico di Padova, Italy), M. Salaris (Liverpool John Moores University, UK), R. M. Rich (University of California Los Angeles, USA), H. Richer (University of British Columbia), J. Anderson (Space Telescope Science Institute, USA), B. Bettoni (INAF-Osservatorio Astronomico di Padova, Italy), D. Nardiello (Università di Padova, Italy), A. P. Milone (Università di Padova, Italy), A. F. Marino (Università di Padova, Italy), M. Libralato (Space Telescope Science Institute, USA), A. Bellini (Space Telescope Science Institute, USA), A. Dieball (University of Bonn, Germany), P. Bergeron (Université de Montréal, Canada), A. J. Burgasser (University of California San Diego, USA), D. Apai (University of Arizona, USA)

Membraneless protocells could provide clues to formation of early life

Membraneless protocells -- called complex coacervates -- can bring together molecules of RNA allowing the RNAs to perform certain reactions, an important step in the origin of life on Earth. The Image shows droplets of complex coacervates as seen under a microscope. The inset shows RNA molecules (cyan) are highly concentrated inside the droplets compared to the surrounding (dark). At roughly 2-5 micrometers in diameter, the droplets are about 14-35 times thinner than human hair.

Membraneless assemblies of positively- and negatively-charged molecules can bring together RNA molecules in dense liquid droplets, allowing the RNAs to participate in fundamental chemical reactions. These assemblies, called "complex coacervates," also enhance the ability of some RNA molecules themselves to act as enzymes -- molecules that drive chemical reactions. They do this by concentrating the RNA enzymes, their substrates, and other molecules required for the reaction. The results of testing and observation of these coacervates provide clues to reconstructing some of the early steps required for the origin of life on Earth in what is referred to as the prebiotic "RNA world." A paper describing the research, by scientists at Penn State, appears January 30, 2019 in the journal Nature Communications.

"We're interested in how you go from a world with no life to one with life," said Philip C. Bevilacqua, Distinguished Professor of Chemistry and of Biochemistry and Molecular Biology at Penn State and one of the senior authors of the paper. "One can imagine a lot of steps in this process, but we are not looking at the most elemental steps. We are interested in a slightly later step, to see how RNA molecules could form from their basic building blocks and if those RNA molecules could drive the reactions needed for life in the absence of proteins."

Life as we know it today generally requires genetic material -- DNA, which is first transcribed into RNA. These two molecules carry information for the production of proteins, which are in turn required for most functional aspects of life, including the production of new genetic material. This sets up a "chicken and the egg" dilemma for the origins of life on early Earth. DNA is required to produce proteins, but proteins are required to produce DNA.

"RNA -- or something similar -- has been thought of as a key to solving this dilemma," said Raghav R. Poudyal, Simons Origins of Life Postdoctoral Fellow at Penn State and first author of the paper. "RNA molecules carry genetic information, but they can also function as enzymes to catalyze the chemical reactions needed for early life. This fact has led to the notion that life on Earth went through a stage where RNA played an active role in facilitating chemical reactions -- "the RNA World" -- where self-replicating RNA molecules both carried the genetic information and performed functions that are now generally carried out by proteins."

Another common feature of life on Earth is that it is compartmentalized in cells, often with an outer membrane, or in smaller compartments inside cells. These compartments ensure that all the components for the chemical reactions of life are in easy reach, but in the prebiotic world the building blocks for RNA -- or the RNA enzymes needed to drive the chemical reactions that could lead to life -- would probably have been scarce, floating around in the primordial soup.

"You can think of these RNA enzymes like a car being produced in an assembly line," said Poudyal. "If you don't have the parts in the right place in the factory, the assembly line doesn't work. Without coacervates, the parts needed for chemical reactions are too dilute and are unlikely to find each other, but inside the coacervates, all the parts that the enzyme needs to work are nearby."

The researchers therefore looked at a variety of materials that may have existed in the pre-life Earth that can form coacervates -- membraneless protocells -- and then allowed critical functions like sequestering the building blocks of RNA and bringing together RNA enzymes and their targets.

"It was previously known that RNA molecules can assemble and elongate in solutions with high concentrations of magnesium," said Poudyal. "Our work shows that coacervates made from certain materials allow this non-enzymatic template-mediated RNA assembly to occur even in the absence of magnesium."

The coacervates are composed of positively charged molecules called polyamines and negatively charged polymers which cluster together to form membraneless compartments in a solution. Negatively charged RNA molecules are also attracted to the polyamines in the coacervates. Within the coacervates the RNA molecules are as much as 4000 times more concentrated than in the surrounding solution. By concentrating the RNA molecules in the coacervates, RNA enzymes are more likely to find their targets to drive chemical reactions.

"Although all the polyamines we tested were able to participate in formation of RNA-rich droplets, they differed in their ability to support RNA elongation," said Christine Keating, professor of chemistry at Penn State and a senior author on the paper. "These observations help us understand how the chemical environment within different membraneless compartments can impact RNA reactions."

"Although we can't look back to see the exact steps taken to form the first life on Earth, coacervates like the ones we can create in the laboratory may have helped by facilitating chemical reactions that otherwise would not have been possible," said Poudyal.

In addition to Bevilacqua, Poudyal, and Keating, the research team at Penn State includes Rebecca M. Guth-Metzler, Andrew J. Veenis, and Erica A. Frankel. The research was supported by the Simons Foundation and NASA.

Huge cavity in Antarctic glacier signals rapid decay

Thwaites Glacier.

A gigantic cavity -- two-thirds the area of Manhattan and almost 1,000 feet (300 meters) tall -- growing at the bottom of Thwaites Glacier in West Antarctica is one of several disturbing discoveries reported in a new NASA-led study of the disintegrating glacier. The findings highlight the need for detailed observations of Antarctic glaciers' undersides in calculating how fast global sea levels will rise in response to climate change.

Researchers expected to find some gaps between ice and bedrock at Thwaites' bottom where ocean water could flow in and melt the glacier from below. The size and explosive growth rate of the newfound hole, however, surprised them. It's big enough to have contained 14 billion tons of ice, and most of that ice melted over the last three years.

"We have suspected for years that Thwaites was not tightly attached to the bedrock beneath it," said Eric Rignot of the University of California, Irvine, and NASA's Jet Propulsion Laboratory in Pasadena, California. Rignot is a co-author of the new study, which was published in Science Advances. "Thanks to a new generation of satellites, we can finally see the detail," he said.

The cavity was revealed by ice-penetrating radar in NASA's Operation IceBridge, an airborne campaign beginning in 2010 that studies connections between the polar regions and the global climate. The researchers also used data from a constellation of Italian and German spaceborne synthetic aperture radars. These very high-resolution data can be processed by a technique called radar interferometry to reveal how the ground surface below has moved between images.

"[The size of] a cavity under a glacier plays an important role in melting," said the study's lead author, Pietro Milillo of JPL. "As more heat and water get under the glacier, it melts faster."

Numerical models of ice sheets use a fixed shape to represent a cavity under the ice, rather than allowing the cavity to change and grow. The new discovery implies that this limitation most likely causes those models to underestimate how fast Thwaites is losing ice.

About the size of Florida, Thwaites Glacier is currently responsible for approximately 4 percent of global sea level rise. It holds enough ice to raise the world ocean a little over 2 feet (65 centimeters) and backstops neighboring glaciers that would raise sea levels an additional 8 feet (2.4 meters) if all the ice were lost.

Thwaites is one of the hardest places to reach on Earth, but it is about to become better known than ever before. The U.S. National Science Foundation and British National Environmental Research Council are mounting a five-year field project to answer the most critical questions about its processes and features. The International Thwaites Glacier Collaboration will begin its field experiments in the Southern Hemisphere summer of 2019-20.

How Scientists Measure Ice Loss

There's no way to monitor Antarctic glaciers from ground level over the long term. Instead, scientists use satellite or airborne instrument data to observe features that change as a glacier melts, such as its flow speed and surface height.

Another changing feature is a glacier's grounding line -- the place near the edge of the continent where it lifts off its bed and starts to float on seawater. Many Antarctic glaciers extend for miles beyond their grounding lines, floating out over the open ocean.

Just as a grounded boat can float again when the weight of its cargo is removed, a glacier that loses ice weight can float over land where it used to stick. When this happens, the grounding line retreats inland. That exposes more of a glacier's underside to sea water, increasing the likelihood its melt rate will accelerate.

An Irregular Retreat

For Thwaites, "We are discovering different mechanisms of retreat," Millilo said. Different processes at various parts of the 100-mile-long (160-kilometer-long) front of the glacier are putting the rates of grounding-line retreat and of ice loss out of sync.

The huge cavity is under the main trunk of the glacier on its western side -- the side farther from the West Antarctic Peninsula. In this region, as the tide rises and falls, the grounding line retreats and advances across a zone of about 2 to 3 miles (3 to 5 kilometers). The glacier has been coming unstuck from a ridge in the bedrock at a steady rate of about 0.4 to 0.5 miles (0.6 to 0.8 kilometers) a year since 1992. Despite this stable rate of grounding-line retreat, the melt rate on this side of the glacier is extremely high.

"On the eastern side of the glacier, the grounding-line retreat proceeds through small channels, maybe a kilometer wide, like fingers reaching beneath the glacier to melt it from below," Milillo said. In that region, the rate of grounding-line retreat doubled from about 0.4 miles (0.6 kilometers) a year from 1992 to 2011 to 0.8 miles (1.2 kilometers) a year from 2011 to 2017. Even with this accelerating retreat, however, melt rates on this side of the glacier are lower than on the western side.

These results highlight that ice-ocean interactions are more complex than previously understood.

Milillo hopes the new results will be useful for the International Thwaites Glacier Collaboration researchers as they prepare for their fieldwork. "Such data is essential for field parties to focus on areas where the action is, because the grounding line is retreating rapidly with complex spatial patterns," he said.

"Understanding the details of how the ocean melts away this glacier is essential to project its impact on sea level rise in the coming decades," Rignot said.

The paper by Milillo and his co-authors in the journal Science Advances is titled "Heterogeneous retreat and ice melt of Thwaites Glacier, West Antarctica." Co-authors were from the University of California, Irvine; the German Aerospace Center in Munich, Germany; and the University Grenoble Alpes in Grenoble, France.