How Cells Communicate in Cell Division

Intricate network of regulatory functions explained Monday, 05 May 2008 A new study reveals how cells communicate to activate the cell division machinery. The finding made in the fruit fly may provide clues to address problems such as the proliferation of malignant cells and tumour growth in humans. The study was performed by researchers at the Institute for Research in Biomedicine (IRB Barcelona) on the fruit fly, Drosophila melanogaster, and unveils how distinct signalling pathways operate between neighbouring cells in order to activate the cell proliferation machinery that results in the organized growth of the fly wing. The signalling pathways involved in this process are also conserved in humans, and when altered in diverse tissues give rise to the appearance of different types of cancer, including cancer of the colon and skin, and leukaemia. The study has been undertaken in the Cell and Development Biology Laboratory headed by ICREA Research Professor Marco Milán, at IRB Barcelona, and has been released in and advanced online format by the EMBO Journal. The researchers have shown that the Notch and Wnt/Wingless signalling pathways exert control over the cell division machinery through two gene effectors, the proto-oncogene dMyc and the micro-RNA bantam. Regulated by Notch and Wnt/Wingless, these two genes instruct another gene, E2F, to activate the cell division machinery. “All the components were already known but we have clarified the order in the signalling cascade and the interaction between the molecular elements that regulate proliferation for the correct development of the wing”, explained Dr. Héctor Herranz, first author of the article. “Diseases like cancer cannot be understood without taking into account how the distinct molecular elements are integrated,” Prof. Milán said. Notch and Wnt/Wingless play a key role in embryo development, cell growth (proliferation) and the transformation of cells into specialized types (differentiation). The interesting feature is that these two pathways are highly conserved in humans and when mutations arise tumours appear. The fruit fly wing is a vital experimental model to find future biomedical applications. Prof. Milán goes on to say that “...this finding could provide clues about how to repress the cell proliferation signals in cancer”. The context is relevant Furthermore, the research has elucidated the relationship between Notch and Wnt/Wingless in the control of proliferation and the development of the fly wing. In fact, Notch has a repressor function, that is to say, when it is activated the cell division machinery is arrested. Only when Wnt/Wingless starts to work is Notch silenced, thereby triggering the cascade of genes that allow proliferation. “Notch works in this context as a tumour suppressor while Wnt/Wingless acts as an oncogene, that is, by cancelling the action of Notch it allows the cell division machinery to operate,” Prof. Milán explains. But the fundamental point for the researchers is that Notch and Wnt/Wingless can interchange their roles depending on the context in which they are operating because the true executors of the action are the genes that these proteins regulate, in this case dMyc and bantam. Researchers ask how, for example, in function of the tissue that is affected, Notch can serve as a “tumour suppressor” or as an oncogene. The conclusions drawn from this study, point to effectors being regulated by this pathway. “We have highlighted the importance of the context in which these signalling pathways work and that knowledge about the underlying regulatory elements is crucial to understand how a certain function is performed”, explains Dr. Herranz. According to Prof. Milán, diseases like cancer cannot be understood without taking into account how the distinct elements are integrated: that is to say, crosstalk between neighbouring cells, effector genes and cell cycle machinery. “Now we must look for similarities in vertebrates and humans to see whether these elements work in the same way in diseases”, he concludes. Reference: A Wingless and Notch double-repression mechanism regulates G1-S transition in the Drosophila wing. Héctor Herranz, Lidia Pérez, Francisco A. Martín, and Marco Milán The EMBO Journal, advance online publication 1 May 2008; doi: 10.1038/emboj.2008.84 ......... ZenMaster

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How Gene Transcription Is Controlled In ESCs

Nanog and Oct4 associate with unique repressor complexes on their target genes to control ES cell fate. Sunday, 04 May 2008 Association determines fate in embryonic stem cells, said Baylor College of Medicine researchers in a report that appears in the current issue of the journal Nature Cell Biology. “These findings provide models of how the embryonic stem cell is maintained in its flexible state,” said Dr. Zhou Songyang, professor of biochemistry and molecular biology at BCM and senior author of the report. “It provides another hint as to how gene transcription is controlled in embryonic stem cells.” One aim of embryonic stem cell research is to understand how the cells determine whether they will keep dividing and maintain a pool of embryonic cells, or start the process of cellular differentiation that results in different cell types. Songyang and his colleagues found that two critical embryonic cell proteins – Nanog and Oct4 – associate with specific components that are parts of transcription repression complexes. These complexes affect the way that genes are expressed and carry out their tasks in the cell. A special complex called NODE (Nanog and Oct4-associated Deacetylase) contains a critical component called Mta1 along with histone deacetylases. NODE associates with Nanog and Oct4 to control the fate of embryonic stem cells, said Songyang. Histones are critical parts of genomic DNA structures or chromatins, acting as “spools” around which the genetic material winds in the nucleus. The DNA wraps more tightly when deacetylase removes the acetyl tails from the histones. The tight wrapping makes it hard for genes to be transcribed into the message that allows them to carry out their roles in the cell. “Think of it as the parts of a car,” said Songyang. “If you think of Nanog as the engine that drives it, you realize that the car still needs accessories like wheels, the tailpipe, etc. We are interested in the big machinery of which proteins (like Nanog) are the drivers. We want to understand the enzymatic activities of the complexes. Then we need to identify the individual parts and ask the big question: ‘How do different parts work together and why do you need special parts’”. “We noticed that there are many histone deacetylases,” he said. “Nanog uses these proteins to control gene expression and maybe also the chromatin state. When there is deacetylation, the gene is in a passive state.” “The embryonic stem cell is always at the stage of deciding whether to divide (and make more embryonic stem cells) or to differentiate,” Songyang said. “All the extrinsic and intrinsic signals make the life of the embryonic stem cell transient. In other words, it has to be ready to go down either road.” “It becomes an interesting question,” said Songyang. “Such a demanding state of readiness may mean that the embryonic stem cell requires a different complex at the chromatin than the somatic (or differentiated cell).” Reference: Nanog and Oct4 associate with unique transcriptional repression complexes in embryonic stem cells Jiancong Liang, Ma Wan, Yi Zhang, Peili Gu, Huawei Xin, Sung Yun Jung, Jun Qin, Jiemin Wong, Austin J. Cooney, Dan Liu & Zhou Songyang Nature Cell Biology, 4 May 2008 doi:10.1038/ncb1736 ......... ZenMaster

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Microchimerism: The Ties That Binds

Mothers and offspring can share cells throughout life — with positive and negative effects 
Friday, 02 May 2008 


Cutting the umbilical cord doesn't necessarily sever the physical link between mother and child. Many cells pass back and forth between the mother and foetus during pregnancy and can be detected in the tissues and organs of both even decades later. This mixing of cells from two genetically distinct individuals is called microchimerism. The phenomenon is the focus of an increasing number of scientists who wonder what role these cells play in the body. A potentially significant one, it turns out. Research implicates that maternal and foetal microchimerism plays both adverse and beneficial roles in some autoimmune diseases as well as the prevention of at least one cancer. This double-edged sword in turn has opened new avenues of study of the body's immune system and the possibility of developing new tests and therapies. 


 Two of the world's leading researchers in microchimerism are J. Lee Nelson, M.D., of Fred Hutchinson Cancer Research Center's Clinical Research Division; and V.K. Gadi, M.D., Ph.D., assistant professor of medicine at the University of Washington. Nelson also is a professor of medicine at the University of Washington. Gadi is also a research associate in the Hutchinson Center's Clinical Research Division. In 2007, they were the first to report these potentially beneficial effects of microchimerism:

• In January, Nelson reported the first discovery that cells passed from mother to child during pregnancy can differentiate into functioning islet beta cells that produce insulin in the child. The same study also found maternal DNA in greater amounts in the blood of children and young adults with Type 1 diabetes than their healthy siblings and a control group, implying that the cells may be attempting to repair damaged tissue. There was no evidence that the mother's cells were attacking the child's insulin cells and no evidence that the maternal cells were targets of an immune response from the child's immune system. The findings could lead to new approaches to treating Type 1 diabetes. For example, if maternal microchimerism results in cells that make insulin, a mother's stem cells might be harvested and used to treat her diabetic child. Such cells would have a genetic edge over donated islet cells from a cadaver that are usually completely genetically mismatched.

• Last October, a research paper by Gadi and Nelson described findings that suggest foetal cells that persist in a woman's body long after pregnancy in some cases may reduce the woman's risk of breast cancer. The scientists examined the blood of 82 women post-pregnancy, 35 of whom had had breast cancer. They looked for male DNA in the blood, presuming it was present due to a prior pregnancy with a male. Foetal microchimerism (FMc) was found significantly more often in healthy women than women with a history of breast cancer, 43 percent versus 14 percent respectively. The scientists concluded that FMc may contribute to the reduction of breast cancer based on the hypothesis that residual foetal cells may provide immune surveillance of malignant cells in the mother. They caution that further studies are needed to confirm the theory.

Microchimerism reveals its Jekyll and Hyde personality in the case of autoimmune diseases. In the late 1990s, Nelson's group was the first to investigate microchimerism in an autoimmune disease:

• In 1996 Nelson's lab proposed that foetal microchimerism might in part explain the female predilection to autoimmune disease and they subsequently discovered elevated levels of foetal microchimerism in the blood of women with scleroderma compared to healthy women. Subsequent studies found foetal microchimerism in internal organs and in skin affected by scleroderma.

• In 1999 Nelson's group found that maternal microchimerism persists into adult life in individuals who have normal immune systems. They presumed this is due to engraftment with maternal stem cells. Stem cells can become multiple different types of cells. Researchers wondered whether maternal cells can become part of the cells that make up tissues. Scientists found maternal cells in the hearts of infants who died from heart block due to neonatal lupus and identified that most of the maternal cells were cardiac myocytes (heart muscle cells). They theorized that the maternal cells are the target of an immune attack.

• On the other hand, women with rheumatoid arthritis often have their disease improve or even disappear during pregnancy. A beneficial role of foetal microchimerism was suggested by the research finding that elevated levels of foetal microchimerism significantly correlated with pregnancy-induced amelioration of rheumatoid arthritis.

The Nelson lab has expanded its study of microchimerism into the fields of reproduction, HIV/AIDS and transplantation. For example, scientists are investigating microchimerism in complications of pregnancy, especially preeclampsia, a disorder characterized by high blood pressure in women in their third trimester of pregnancy, and in recurrent pregnancy loss. Nelson's group also is investigating maternal microchimerism in patients with HIV and is looking at whether maternal microchimerism levels correlate with whether there is progression or non-progression to AIDS. Transplantation of stem cells to treat some cancers results in chimerism. Graft-vs.-host disease occurs more often if the cell donor is a woman with prior pregnancies. 


Tests of female donor cells found they contained male microchimerism, consistent with the interpretation that foetal microchimerism contributes to graft-vs.-host disease. In kidney, pancreas and islet transplantation, Gadi, Nelson and collaborators tested serial serum samples and found that donor-specific microchimerism detection may become a useful non-invasive test for early rejection. This has led to work by several other research groups to therapeutically exploit the principles of naturally-acquired microchimerism in their selection of donors for transplantation. 


The discovery that a mother's cells can turn up in her adult progeny and that foetal cells can occur in women who were once pregnant heralds the emergence of microchimerism as an important new theme in biology.


About Fred Hutchinson Cancer Research Center At Fred Hutchinson Cancer Research Center, our interdisciplinary teams of world-renowned scientists and humanitarians work together to prevent, diagnose and treat cancer, HIV/AIDS and other diseases. Our researchers, including three Nobel laureates, bring a relentless pursuit and passion for health, knowledge and hope to their work and to the world. 
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