Production of offspring from a germline stem cell line derived from neonatal ovaries.
Zou K, Yuan Z, Yang Z, Luo H, Sun K, Zhou L, Xiang J, Shi L, Yu Q, Zhang Y, Hou R, Wu J.
School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China.
Nat Cell Biol. 2009 Apr 12
During embryonic development in human females and most mammalian species, cells in the ovary called oogonia proliferate by numerous mitotic divisions to form primary oocytes. About one million form per ovary. These begin the fist meiotic division and then stop before the birth of the female in a prolonged diplonema stage called the dictyotene. A primary oocyte does not resume meiosis until the female is past puberty, when under hormonal control, ovulation takes place. This process usually occurs for only one oocyte per month during the female’s entire reproductive lifespan (from twelve to fifty years of age). The first meiotic division is completed and this is followed by the second meiotic division, thus completing the process of gamete formation in the female.
However, the idea that females have lost the capacity for oocyte production at birth has been challenged by this article which gives evidence for the existence of female germline stem cells (FGSCs) in postnatal mammalian ovaries. The authors have isolated FGSCs from young and adult mice and cultured them for more than 6 months. These FGSCs were infected with a green fluorescent protein (GFP) virus and transplanted into ovaries of infertile mice. Eighty percent of these mice went on to produce offspring that had the GFP transgene after natural mating.
This finding, if corroborated by other researchers, may help infertile women conceive and have children. A question that comes to mind is: do infertile women have FGSCs in their ovary? If the answer is “yes”, how can they be stimulated to undergo oogenesis? On the other hand, if the answer is “no”, then treatment will involve transplantation of FGSCs from a donor to the infertile recipient, in which case immunosuppression may be required to prevent rejection. Another possible application would be in prolonging the reproductive lifespan of women. Generation of new oocytes could help older women conceive. In addition, it could be a boon for those with premature ovarian failure.
Sunday, April 19, 2009
Monday, April 13, 2009
A new target for cancer therapy.
An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer
Teresa A. Soucy et al.
Nature 458, 732-736 (9 April 2009)
This group of authors has discovered a compound that inhibits the never-before-targeted NEDD8-activating enzyme (NAE), and show that this compound suppresses the growth of human lung-tumour tissue transplanted into mice.
The new drug principally targets the ubiquitin-proteasome system (UPS). One of main disadvantages in targeting the UPS is its non-specificity. A wide variety of vital cellular processes are intimately liked to the UPS. However, the UPS was shown to be a effective target for cancer chemotherapeutics when Bortezomib, a E3 ligase inhibitor, was successfully developed for the treatment of refractory multiple myeloma.
This paper reports a clever way around the problem of non-specificity of the UPS. Instead of targeting E3 ligase enzymes directly, they targeted NEDD8-activating enzyme (NAE), which is required to activate a subset of E3 enzymes known as cullin-RING ubiquitin ligases (CRLs). Inhibition of NAE leads to the accumulation of the substrates of CRLs in the cell. This induced apoptosis in the proliferating cancer cells possibly as a result of the deregulation of DNA synthesis. This phenomenon was already seen in vitro when cancer cell lines were exposed to this drug. What is most interesting and promising is the fact that the authors report nearly complete regression of transplanted human lung-tumour tissue in the drug-treated mice, with no obvious side effects. It remains unclear, however, why a drug that inactivates so many different CRLs (presumably also those in healthy cells) should kill only cancer cells.
These are exciting findings, but it is prudent to remember that many promising drug candidates have been shown to cure cancer in mice, only to fail spectacularly in humans. It remains to be seen whether it will become the second marketed drug that deliberately targets components of the UPS after Bortezomib.
Teresa A. Soucy et al.
Nature 458, 732-736 (9 April 2009)
This group of authors has discovered a compound that inhibits the never-before-targeted NEDD8-activating enzyme (NAE), and show that this compound suppresses the growth of human lung-tumour tissue transplanted into mice.
The new drug principally targets the ubiquitin-proteasome system (UPS). One of main disadvantages in targeting the UPS is its non-specificity. A wide variety of vital cellular processes are intimately liked to the UPS. However, the UPS was shown to be a effective target for cancer chemotherapeutics when Bortezomib, a E3 ligase inhibitor, was successfully developed for the treatment of refractory multiple myeloma.
This paper reports a clever way around the problem of non-specificity of the UPS. Instead of targeting E3 ligase enzymes directly, they targeted NEDD8-activating enzyme (NAE), which is required to activate a subset of E3 enzymes known as cullin-RING ubiquitin ligases (CRLs). Inhibition of NAE leads to the accumulation of the substrates of CRLs in the cell. This induced apoptosis in the proliferating cancer cells possibly as a result of the deregulation of DNA synthesis. This phenomenon was already seen in vitro when cancer cell lines were exposed to this drug. What is most interesting and promising is the fact that the authors report nearly complete regression of transplanted human lung-tumour tissue in the drug-treated mice, with no obvious side effects. It remains unclear, however, why a drug that inactivates so many different CRLs (presumably also those in healthy cells) should kill only cancer cells.
These are exciting findings, but it is prudent to remember that many promising drug candidates have been shown to cure cancer in mice, only to fail spectacularly in humans. It remains to be seen whether it will become the second marketed drug that deliberately targets components of the UPS after Bortezomib.
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