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RESEARCH BRIEFSBreast Cancer Role for Prolyl Isomerase Pinned DownThe prolyl isomerase Pin1, which can cause conformational changes in proteins through the cis–trans isomerization of the cyclical amino acid proline, is known to be essential for mitosis. However, its role in tumor development, if any, has remained untested. Recent work from the lab of Kun Ping Lu, HMS assistant professor of medicine at Beth Israel Deaconess Medical Center, shows that this enzyme may be a key regulator of proteins that promote breast cancer.
Pin1 does double duty in boosting cyclin D1. The prolyl isomerase Pin1 increases the activity of c-Jun and beta-catenin in the nucleus. These transcription factors in turn drive expression of the cyclin D1 gene upon binding to its upstream activator sites, AP-1 and TCF1. Adapted by Jeff Cleary from original by Kun Ping Lu The first hint of Pin1's role came when Gerburg Wulf, HMS instructor in medicine, and colleagues from the Lu lab, working in collaboration with Sam Lee, HMS assistant professor of medicine at BID, found the isomerase is overexpressed in human breast cancers. In the July 2 EMBO Journal, they report that this upregulation correlates with an increase in levels of cyclin D1, a cell cycle protein previously shown to be essential for induction of breast tumors by the oncogenes v-Ha-Ras and c-Neu. The researchers also showed that increased levels of D1 are due to the selective activation, by Pin1, of the AP-1 promoter site, which controls transcription of the D1 gene. This activation was traced to an interaction between Pin1 and the AP-1 binding protein c-Jun; Pin1 appears to isomerize phosphorylated c-Jun, potentiating its effect on transcription. But the relationship between Pin1 and cyclin D1 does not stop there. In September's Nature Cell Biology, Akihide Ryo and Lu team members report that the prolyl isomerase increases levels of another D1 activator, beta-catenin. This transcription factor, when bound to the tumor suppressor protein APC, is usually shuttled from the nucleus to the cytoplasm, where it is destroyed. Pin1 interferes with this process by compromising beta-catenin's APC-binding site, causing beta-catenin to accumulate in the nucleus, where it can activate D1 through a second promoter site, dubbed TCF1.
Plasma Cell Activator RevealedChallenges to mammalian immune systems elicit a wide variety of cellular responses. When B lymphocytes are activated, for example, they can specialize by differentiating into memory B cells or immunoglobulin-secreting plasma cells. Though much is known about the early steps in B-cell activation, little is known about the final steps leading to formation of plasma cells. In the July 19 Nature, HSPH researchers Andreas Reimold and Neal Iwakoshi, working under the direction of Laurie Glimcher, the Irene Heinz Given professor of immunology at HSPH and an HMS professor of medicine at Brigham and Women's Hospital, report that X-box-binding protein-1 (XBP-1) may be specifically required for this process. Together with colleagues from Harvard, the University of Massachusetts Medical Center, and Howard Hughes Medical Institute, they found that this transcription factor is upregulated in plasma cells of rheumatoid arthritis patients and showed that this effect could be due to signal transduction through one of the key molecules in B-cell activation, the CD40 cell surface receptor; activation of CD40 not only caused differentiation of B cells but was found to increase transcription of XBP-1. In addition, overexpression of XBP-1 in a B-cell line caused expression of Syndecan-1 and a decrease in CD44 levels, responses typically associated with plasma cell differentiation. The authors used chimeric mice to further pinpoint the function of XBP-1 in the immune response. XBP-1-negative chimeras had normal development of lymph, spleen, and B- and T-cell types, however, they had much lower serum immunoglobulin (Ig) levels than wild-type mice and failed to respond to Ig-boosting antigens. In fact, when XBP-1-negative B cells were activated in vitro, the response was virtually indistinguishable from that of wild-type B cells; cell surface markers, proliferation, cytokine secretion, and immunoglobulin class switching were all normal. These cells were only compromised by lacking expression of immunoglobulin J-chain and in failing to downregulate c-myc, two key properties associated with differentiation into plasma cells.
Tumor Suppressors Team Up in ApoptosisAlthough the epithelium of the small intestine is one of the most rapidly proliferating human tissues, the incidence of cancer in this part of the gastrointestinal tract is relatively low. An exception to the rule occurs in people with Peutz-Jeghers syndrome (PJS), which first appears as excessive pigmentation of mucous membranes, including lips and gums, and later in life as increased susceptibility to cancerous polyps of the small intestine. Though the gene responsible for this disease, LKB1, is thought to be a tumor suppressor, its exact mode of action is unclear. Researchers from the laboratory of Junying Yuan, HMS professor of cell biology, report in June's Molecular Cell that LKB1 may be a moderator of programmed cell death. Visiting scientist Philip Karuman and colleagues, working in collaboration with Lewis Cantley, HMS professor of medicine at Beth Israel Deaconess Medical Center, found that LKB1 expression is higher in older epithelial cells, which undergo apoptosis after migration to the tip of the villi in the small intestine. The researchers also found that LKB1 expression is absent in intestinal polyps of PJS patients. More direct evidence for an apoptotic role came when the researchers overexpressed LKB1 in a fibrosarcoma cell line; the tumor suppressor induced cell death in a manner that depended on caspases, proteases linked to apoptosis. The researchers were able to demonstrate that the action of LKB1 was mediated by p53, another well-known tumor suppressor and player in apoptosis. The PJS protein could induce apoptosis in fibroblasts but only in the presence of p53. Furthermore, immunoprecipitation experiments indicated that the two proteins directly associate, an interaction that was stronger when cells were treated with the apoptosis-inducing drug paclitaxel. These tumor suppressors may conspire to induce apoptosis since, in the absence of p53, LKB1 failed to translocate to the mitochondria, where programmed cell death is initiated. —Briefs above by Tom Fagan
Is It Safe to Go Back in the Water?While swimming this summer, sharks are the least of your worries. Of more immediate risk may be the bacteria, viruses, protozoa, and plankton, depending on where you happen to be, says a review of marine swimming-related illness, which appears in the July Environmental Health Perspectives. From 1988 to 1994, more than 12,000 U.S. coastal beaches closed or issued advisories, most due to microbial contamination that could in many cases be traced back to sewage. Submerged swimmers are sitting ducks for pathogens, toxins, and irritants that can easily enter the ears, eyes, nose, and mouth, as well as the anus and genitourinary tract, the paper says. Moreover, nearly 100 percent of the skin is directly exposed to infectious agents and toxic chemicals through swimming or working in polluted waters. This exposure can lead to a variety of health problems, including dermatitis and skin infections or deep tissue and blood infection through open cuts. "We are not adequately applying scientific advances to public policy, so we are not sufficiently protecting ourselves from the public health impacts of marine degradation, nor are we collecting the data necessary to design appropriate regulations, such as defining acceptable pathogen levels," says first author Sarah Henrickson, who is deferring her first year in the HMS MD–PhD program and spending the year working at the NIH. Water quality monitoring techniques are lagging despite mounting evidence of exposure, says senior author Paul Epstein, associate director of the HMS Center for Health and the Global Environment and an instructor in medicine. Epstein and his co-authors call for better water quality monitoring that takes into account new understanding of the biology and long lives of some pathogens, as well as new molecular and cell culture techniques. Health system surveillance needs to be integrated with marine ecosystem monitoring, say the authors. And local, national, and international regulations on such critical issues as fishing, waste release, coastal degradation, and carbon dioxide must be strengthened and enforced. —Carol Cruzan Morton |
