Using an approach that randomly alters expression of mammalian cell genes, together with a screen that detects altered gene function, Dr. Cohen and colleagues identified a previously uncharacterized gene, called txr1, whose increased expression in prostate cancer cells confers resistance to taxane drugs. Taxanes are a class of widely-used chemotherapeutics (marketed as docetaxel and paclitaxel) that prevent cancer cell growth by inhibiting microtubule breakdown and subsequent cell division.

The researchers determined that txr1 promotes taxane resistance by suppressing the known anti-angiogenic and pro-apoptotic factor, thrombospondin 1 (TSP-1). This action is entirely different from mechanisms found earlier to be involved in resistance to taxanes.

Furthermore, they discovered that depletion of txr1, or treatment with TSP-1 (or a TSP-1 mimetic) restores taxane sensitivity. As acquired drug resistance poses a major limitation to the long-term efficacy of taxanes, the discovery of txr1 as a component of a novel pathway of taxane cytotoxicity opens up a new avenue to modulate chemotherapeutic drug response and sensitize cancer cells to drug treatment.

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To examine global DNA methylation patterns in human embryonic stem cells, the researchers analyzed 14 human embryonic stem cell lines from diverse ethnic origins, derived in several different labs, and maintained for various times in culture. They tested over 1500 potential methylation sites in the DNA of these cells and in other cell types and found that the embryonic stem cells shared essentially identical methylation patterns in a large number of gene regions. Furthermore, these methylation patterns were distinct from those in adult stem cells, differentiated cells, and cancer cells.

"Our results suggest that therapeutic cloning of patient-specific human embryonic stem cells will be an enormous challenge, as nuclei from adult cells will have to be epigenetically reprogrammed to reflect the specific DNA methylation signature of normal human embryonic stem cells," explains Dr. Jeanne Loring, co-director of the stem cell center at BIMR. "This reinforces the need for basic research directed at understanding the fundamental biology of human embryonic stem cells before therapeutic uses can be considered."

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