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March, 2011---------News Archive

Twist! Protein Key to Embryo, Linked To Cancer

Twist! protein is key to early embryonic development, but later promotes the spread of cancer.


Early in human embryo formation, a transcription factor called Twist! plays a key role in regulating how the embryo assumes its form and function. However, much later in life Twist! turns more deadly.

Published March 15, 2011 in Cancer Cell, University of California San Diego School of Medicine researchers reveal that Twist! can re-merge later in life to promote the formation of invadopodia on tumor cells.

Invadopodia - or invasive feet - are protrusions of the cell membrane of cells rich in actin which extend into the extracellular matrix (ECM). Invadopodia are also vital to the spread of cancer (metastasis) through-out the body. These tiny protrusions extend into the extracellular matrix - the surrounding connecting tissue and fibers that support normal tissues. Twist! is linked to aggressive, solid-tumor cancers such as melanomas, neuroblastoma, breast and protate cancer.

Assistant professor of Pharmacology and Pediatrics at UCSD, Jing Yang's new research describes in detail how Twist! initiates it's multi-step pathway leading to the formation of invadopodia and the ultimate destruction of the matrix. His research has opened up potential targets for anti-metastasis therapies.

"We hope to inhibit downstream targets of Twist! - such as platelet derived growth factor receptors - to inhibit invadapodia formation and function," says Yang. "Our study suggests that inhibition of invadapodia could be an effective way to suppress metastatis."

If this happens, cancer tumors become stable and unmoving targets for these types of therapeutic treatments.

Research funding came, in part, from the National Institutes of Health, the Sydney Kimmel Foundation for Cancer Research, the California Breast Cancer Research Program and the Susan G. Komen Foundation.

Co-authors of the paper include Mark A. Eckert and Andrew T. Chang, UCSD Molecular Pathology Graduate Program and Biomedical Science Graduate Program; Thinzar M. Lwin and Etienne Danis, UCSD Department of Pharmacology; and Jihoon Kim and Lucila Ohno-Machado, UCSD Division of Biomedical Informatics.

Iron Deficiency Harms Pre-Conception and Early Pregnancy Brain

University of Rochester Medical Center researchers identify window of vulnerability in fetal development.

A mother’s iron deficiency early in pregnancy may have a profound and long-lasting effect on the brain development of the child, even if the lack of iron is not enough to cause severe anemia, according to a University of Rochester Medical Center study published in the scientific journal PLoS One.

The results are important because obstetricians might not notice or treat mild or moderate iron deficiency, and therefore the study authors believe their research underscores the need for monitoring a pregnant woman’s iron status beyond anemia.

Low iron is so common that an estimated 35 percent to 58 percent of all healthy women show some degree of deficiency. And among women of childbearing age, one in five has iron-deficient anemia, a more serious condition, according to the National Institutes of Health.

It is well established that iron-deficient babies develop more slowly and show brain abnormalities such as slow language learning and behavioral problems. But until now investigators did not know the degree to which iron deficiency in pregnancy is associated with these impairments, and when during gestation the deficiency has the most impact on the central nervous system.

“What convinced us to conduct the present study were our preliminary data suggesting that cells involved in building the embryonic brain during the first trimester were most sensitive to low iron levels,” said Margot Mayer-Proschel, Ph.D., the lead researcher and an associate professor of Biomedical Genetics at URMC.

Investigators, therefore, sought more details using a highly controlled animal model system, as it would not be feasible to study iron concentrations in developing human embryos. They found that the critical period begins in the weeks prior to conception and extends through the first trimester to the onset of the second trimester. Iron deficiency that starts in the third trimester did not seem to harm the developing brain.

“This information is very important for clinical care,” said Monique Ho, M.D., a collaborator on the study and assistant professor of Obstetrics and Gynecology and Pediatrics at URMC. “Prenatal care usually involves the recommendation of a multivitamin that contains iron, which is usually prescribed after pregnancy is confirmed or at the first prenatal visit. But not all women have access to prenatal care, and not all women can take the supplements in early pregnancy due to vomiting. This study suggests it might be prudent to begin routine monitoring to detect iron deficiency earlier.”

By studying the relationship between maternal iron intake and fetal iron levels through a diet study, the team was able to pin down the critical periods of gestation when the developing central nervous system was most vulnerable. They measured the resulting brain function using a common, non-invasive test called an auditory brainstem response analysis, or ABR.

Co-author Anne Luebke, Ph.D., an associate professor of Biomedical Engineering and Neurobiology & Anatomy at UR, suggested and directed the use of ABR testing, which can detect the speed of information moving from the ear to the brain. Investigators hoped to learn about impairments or changes in myelin, the insulating material that surrounds axons and is required for normal brain function.

“In addition, ABR testing is routinely performed on human infants, and thus our study has an important component that can be translated to a clinical setting,” Luebke said.

The most surprising aspect of the research, Mayer-Proschel said, was that the timing of the iron deficiency was much more important than the degree of deficiency. This observation also seems to argue against the common notion that the placenta can minimize the impact of the mother’s deficiency on the baby.

“We refer to this as the window of vulnerability,” she said, “and it seems to be at a very early stage of development.” In previous studies of the cellular targets of iron deficiency, Mayer-Proschel found that lack of iron sets off an imbalance of neural precursor cells, which might ultimately be responsible for the defects sometimes experienced by children up to age two.

“The next goals will be to better understand how maternal iron deficiency causes these changes in the offspring,” she said, “and most importantly, what are the opportunities for reversing the damage.”

The National Institutes of Health and the University of Rochester funded the research.

Chemo Causes More Infertile Women Than Men

Chemotherapeutic agents, used in cancer treatment, destroy not only cancer cells but also healthy cells, affecting germ (sex) cells as well.

After surviving cancer, many female patients are confronted with the diagnosis of infertility. For a long time a relationship between infertility and chemotherapeutic agents has been assumed, but until now, the exact mechanism was not known.

Scientists from the research group of Prof. Volker Dötsch (Institute of Biophysical Chemistry, Goethe University Frankfurt) in cooperation with international partners have now started to unveil the mechanism of cancer treatment related infertility.

Their results are published in the internationally renowned journal Cell. Mainly women suffer from infertility because the quality control in eggs (oocytes) is different from male germ cells (sperm).

Male germ cells are produced throughout the whole life span but the number of female germ cells is restricted and slower. If the oocytes are damaged during cancer treatment, they are destroyed by the female's own internal quality control system.

Essential to that process is the protein p63 which shows striking similarity to another important protein of the same family - p53. The protein p53 is called the "guardian of the genome" because it regulates the function of cell division and cell death in damaged cells. It suppresses genetic irregularities which could lead to cancer. In more than half of all human tumors p53 is altered and no longer functioning.

For a long time p53 and p63, their similarities and differences, have been studied in international research. It is currently accepted that healthy cells have a low concentration of p53. But gene anomalies break the DNA chain and reform its strands, p53 changes into a tetramer.

In this state it becomes active and initiates either repair of the damaged DNA or promotes cell death. Surprisingly, despite the fact that p53 and p63 show a lot of similarity, contol of p63 in oocytes seems to be different.

The level of p63 in normal oocytes is high and the protein is kept in a closed dimeric - or inactive state.

If DNA double-strand breaks occur, for example caused by radiation, p63 becomes phosphorylated and it's structure changes. The resulting p63 tetramer is similar to the p53 tetramer and leads to the death of the oocyte. Many chemo therapy agents cause DNA double-strand breaks in p63 and ultimately to the death of eggs.

In looking at the model organism, the tiny worm called Caenorhabditis elegans (or C elegans), the Dötsch group noted that due to the short life span - the worm only lives 3 weeks - p63 does not act as a tumor suppressor but instead controls the eggs' genetic stability. This may have been the original function of the p53 protein - and leads to the speculation that p63 is the ancestor of the entire p53 family.

Interestingly, p63 is also essential for the maintenance of stem cells in epithelial skin cells. Because of the close similarity of stem cells and germ cells, this adds to the evidence for evolution of p63 into p53-like proteins, underlining the importance of the both proteins to human health.

Prof. Dr. Volker Dötsch, Institute for Biophysical Chemistry, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, phone: +49 69 798 29631, email: vdoetsch@em.uni-frankfurt.de, Correspondence: DOI 10.1016/j.cell.2011.01.013

Publication: Deutsch et al., DNA Damage in Oocytes Induces a Switch of the Quality Control Factor TAp63a from Dimer to Tetramer, Cell (2011), doi:10.1016/j.cell.2011.01.013

Mother's Obesity May Lead to Child's Infertility

Levels of the hormone ghrelin are low in obese women and a recent study accepted for publication in Endocrinology, a publication of The Endocrine Society, reports that mice whose mothers had low ghrelin levels were less fertile due to a defect in implantation.

Hormones involved in energy balance and metabolism, such as ghrelin, have been shown to regulate reproductive function in animals and humans. However ghrelin's role in reproductive tract development remains unclear. The current study examined the effect of ghrelin deficiency on the developmental programming of female fertility.

"While our study involved mice, we believe our findings have significant implications for women," said Hugh Taylor, MD, of the Yale University School of Medicine in New Haven, Conn. and lead author of the study. "Our results suggest that low ghrelin levels could program the development of the uterus in the female children of obese women. These women may then be less fertile as adults."

In this study, researchers observed that female mice born of mice with ghrelin deficiency had diminished fertility and produced smaller litters than mice born of mice with normal ghrelin levels. Mice exposed to ghrelin deficiency in-utero demonstrated alterations in uterine gene expression which lead to impaired embryo implantation and consequently low fertility.

Other researchers working on the study include: J. Ryan Martin, Sarah Lieber, James McGrath, Marya Shanabrough and Tamas Horvath of the Yale University School of Medicine in New Haven, Conn.

The article, "Maternal Ghrelin Deficiency Compromises Reproduction in Female Progeny through Altered Uterine Developmental Programming," appears in the April 2011 issue of Endocrinology.

Founded in 1916, The Endocrine Society is the world's oldest, largest and most active organization devoted to research on hormones and the clinical practice of endocrinology. Today, The Endocrine Society's membership consists of over 14,000 scientists, physicians, educators, nurses and students in more than 100 countries. Society members represent all basic, applied and clinical interests in endocrinology. The Endocrine Society is based in Chevy Chase, Maryland.















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