Sci. Aging Knowl. Environ., 17 March 2004
Hop on Board
Blueprint for fat-cell specialization hitches a ride from a shuttle protein
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2004/11/nf29
BANFF, CANADA--Taking the bus instead of walking encourages fat storage, and a cellular version of public transit might also cultivate blubber. A protein that carries messenger RNAs (mRNAs) around the cell totes the instructions for a protein that plays a key role in the beginning stages of fat-cell maturation, according to new work presented here 6 March 2004 at the Molecular Control of Adipogenesis and Obesity Keystone Symposium. The work illuminates a previously uninvestigated control point in fat-cell specialization and suggests a possible new target for drugs to shrink flab.
Obesity increases the risk for type II diabetes and other afflictions. To discern how fat accumulates, researchers have studied the process by which cultured precursor cells specialize into mature fat-storing cells when exposed to a particular chemical mixture. Many researchers have focused on pinpointing the genes that perk up at various times during this process. But gene activity can be controlled in other ways, too. For instance, mRNAs must be trucked from the nucleus to the cytoplasm before they can be translated into proteins, and cells can speed or slow this process.
In the new work, Gantt and colleagues looked for passengers that HuR, a protein that escorts mRNA molecules, might pick up. They found a stretch of DNA that HuR grabs next to a gene called C/EBP, which plays a crucial role in fat-cell specialization. That finding suggested that HuR might transport C/EBP mRNA. The researchers investigated HuR's role in fat-cell maturation. First, they confirmed that HuR binds to C/EBP mRNA molecules in a test tube. Next, they showed that triggering specialization of fat-cell precursors caused HuR to leave the nucleus and move to the cytoplasm. They then collected cytoplasm from cells at various points during fat-cell development, fished out HuR molecules with an antibody, and identified the mRNA molecules that rode along. Two hours after the addition of chemicals that spur fat-cell maturation, HuR started clinging to C/EBP mRNA, suggesting that the protein helps transport the molecule. Later in the process, HuR glommed onto mRNA from a different fat-maturation gene. The protein doesn't shepherd all mRNAs. Those from some other genes that also crank up early in fat-cell specialization don't adhere to it, suggesting that HuR targets mRNAs from certain genes. The researchers propose that HuR-assisted C/EBP shuttling is a crucial step in fat-cell maturation and that blocking it might curtail obesity and prevent diabetes. Other RNA transport proteins help muster molecules that spark synthesis of protein from mRNA once it gets to the cytoplasm, and Gantt and colleagues postulate that HuR might serve this role for C/EBP, in addition to carrying it out of the nucleus.
In studying fat-cell development, "people usually think about gene activity rather than how translation [of mRNA] is controlled," says molecular biologist Sheila Collins of Duke University in Durham, North Carolina. "It's an underappreciated area," and the new finding should spark interest in how steps other than mRNA production guide developing fat cells, she says. If future work reveals that cells can't mature without HuR, drugs that tie up the protein might leave mRNAs that nurture fat cells on the curb and help obese people lose weight.
March 17, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150