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Bad neighbors
News & Comment
TRENDS in Cell Biology Vol.11 No.1 January 2001
15
Bad neighbors Chromosome rearrangements play a direct role in development of cancer by bringing gene fragments together to form oncogenic fusion proteins. Certain rearrangements involve genes widely separated in the genome and occur very frequently; but why? One possibility is that the troublemaking genes might be nonrandomly close together in the nucleus, making them more likely to recombine1. In victims of the Chernobyl disaster, the RET proto-oncogene is frequently made oncogenic by an inversion that fuses it to the H4 gene, leading to thyroid tumors. Using FISH, Nikiforova and coworkers found that RET and H4, which are 30 Mb apart on chromosome 10, are nonrandomly close together in normal thyroid cells2. By contrast, the distance
between RET and a locus lying between RET and H4, which does not normally recombine with the RET locus, is apparently random. The Philadelphia chromosome is a translocation between chromosomes 9 and 22 that fuses two ordinarily innocuous genes, BCR and ABL, to create the BCR–ABL oncogene. This rearrangement is seen in 95% of patients with chronic myelogenous leukemia. Kozubek and colleagues3 used FISH to show that chromosomes 9 and 22 are nonrandomly close to each other in the nucleus. Theoretical modeling showed that this proximity could account for the high frequency of translocations between these two chromosomes. These studies suggest that nuclear architecture plays a determinative role in
cancer-related chromosome rearrangements. Understanding the etiology of these rearrangements will require a more complete understanding of order within the nucleus. 1 Sachs, R.K. et al. (2000) Radiation-produced chromosome aberrations: colourful clues. Trends Genet. 16, 143–146 2 Nikiforova, M.N. et al. (2000) Proximity of chromosomal loci that participate in radiationinduced rearrangements in human cells. Science 290, 138–141 3 Kozubek, S. et al. (1999)The topological organization of chromosomes 9 and 22 in cell nuclei has a determinative role in the induction of t(9,22) translocations and in the pathogenesis of t(9,22) leukemias. Chromosoma 108, 426–435
Wallace F. Marshall [email protected]
Steroid hormones send a signal When many of us think of steroid hormones and their receptors, our mind leaps to the nucleus, with images of receptors binding to DNA and regulating gene transcription. In recent years, an onslaught of investigations has forced new, but still fuzzy, images into our brains of steroid hormone action outside of the nucleus. Although decades ago it was noticed that steroids have important non-genomic physiological consequences, and the anti-atherosclerotic affect of estrogen is particularly important for post-menopausal women receiving hormone-replacement therapy, it has only been in the past few years that the cytoplasmic pass-times of steroid hormone receptors have been subject to intensive molecular investigation. The protective effect of estrogen on the cardiovascular system is most likely due to its ability to rapidly stimulate nitric oxide synthase (eNOS) activity in vascular endothelial cells, which leads to their dilation and reduces atherosclerosis. A precise molecular explanation for this observation has been provided by two recent papers1,2 showing that estrogen-induced eNOS activity in vascular endothelial cells is mediated by the cytoplasmic signaling molecules phosphoinositide 3-kinase (PI3K) and AKT, supplanting all doubt that this presumed http://tcb.trends.com
transcription factor is smack in the middle a pathway hitherto thought to consist of only ‘bona fide’ signaling molecules. Simoncini et al. show that estrogen exerts vascular protection following ischemia and reperfusion injury by activating PI3K and eNOS. Most striking is their finding that, in the presence of estrogen, immunoprecipitates of the estrogen receptor (ER) contain the PI3K regulatory subunit p85 and PI3K activity. Both groups show that estrogen stimulation leads to AKT activation in a PI3K-dependent manner, and evidence from Hisamoto and colleagues indicates that AKT activation is mediated by only ER-α, suggesting that the different ER family members participate in separate physiological events. Magnifying the significance of these studies is the finding that PI3K activity is not just found in estrogen receptor
immunoprecipitates but also in precipitates of the thyroid and glucocorticoid receptors1. This suggests that PI3K, which already has been implicated in practically every signaling pathway imaginable, also plays a part in the rapid and transcription-independent effects of several steroid hormones and might be an important target for designing therapies for atherosclerosis. 1 Simocini,T. et al. (2000) Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH-kinase. Nature 407, 538–541 2 Hisamoto, K. et al. Estrogen induces the Aktdependent activation of endothelial nitric oxide synthase in vascular endothelial cells. J. Biol. Chem. (in press)
Kirsten Sadler [email protected]
Letters to Trends in Cell Biology Trends in Cell Biology welcomes your correspondence about articles published in the journal or any topic of general interest to cell biologists. Please take the opportunity to air your views! Letters should be as concise as possible and no more than 700 words long, with up to one figure and 10 references. They can be sent by e-mail to: [email protected] and will be published at the discretion of the Editor.
TRENDS in Cell Biology Vol.11 No.1 January 2001
15
Bad neighbors Chromosome rearrangements play a direct role in development of cancer by bringing gene fragments together to form oncogenic fusion proteins. Certain rearrangements involve genes widely separated in the genome and occur very frequently; but why? One possibility is that the troublemaking genes might be nonrandomly close together in the nucleus, making them more likely to recombine1. In victims of the Chernobyl disaster, the RET proto-oncogene is frequently made oncogenic by an inversion that fuses it to the H4 gene, leading to thyroid tumors. Using FISH, Nikiforova and coworkers found that RET and H4, which are 30 Mb apart on chromosome 10, are nonrandomly close together in normal thyroid cells2. By contrast, the distance
between RET and a locus lying between RET and H4, which does not normally recombine with the RET locus, is apparently random. The Philadelphia chromosome is a translocation between chromosomes 9 and 22 that fuses two ordinarily innocuous genes, BCR and ABL, to create the BCR–ABL oncogene. This rearrangement is seen in 95% of patients with chronic myelogenous leukemia. Kozubek and colleagues3 used FISH to show that chromosomes 9 and 22 are nonrandomly close to each other in the nucleus. Theoretical modeling showed that this proximity could account for the high frequency of translocations between these two chromosomes. These studies suggest that nuclear architecture plays a determinative role in
cancer-related chromosome rearrangements. Understanding the etiology of these rearrangements will require a more complete understanding of order within the nucleus. 1 Sachs, R.K. et al. (2000) Radiation-produced chromosome aberrations: colourful clues. Trends Genet. 16, 143–146 2 Nikiforova, M.N. et al. (2000) Proximity of chromosomal loci that participate in radiationinduced rearrangements in human cells. Science 290, 138–141 3 Kozubek, S. et al. (1999)The topological organization of chromosomes 9 and 22 in cell nuclei has a determinative role in the induction of t(9,22) translocations and in the pathogenesis of t(9,22) leukemias. Chromosoma 108, 426–435
Wallace F. Marshall [email protected]
Steroid hormones send a signal When many of us think of steroid hormones and their receptors, our mind leaps to the nucleus, with images of receptors binding to DNA and regulating gene transcription. In recent years, an onslaught of investigations has forced new, but still fuzzy, images into our brains of steroid hormone action outside of the nucleus. Although decades ago it was noticed that steroids have important non-genomic physiological consequences, and the anti-atherosclerotic affect of estrogen is particularly important for post-menopausal women receiving hormone-replacement therapy, it has only been in the past few years that the cytoplasmic pass-times of steroid hormone receptors have been subject to intensive molecular investigation. The protective effect of estrogen on the cardiovascular system is most likely due to its ability to rapidly stimulate nitric oxide synthase (eNOS) activity in vascular endothelial cells, which leads to their dilation and reduces atherosclerosis. A precise molecular explanation for this observation has been provided by two recent papers1,2 showing that estrogen-induced eNOS activity in vascular endothelial cells is mediated by the cytoplasmic signaling molecules phosphoinositide 3-kinase (PI3K) and AKT, supplanting all doubt that this presumed http://tcb.trends.com
transcription factor is smack in the middle a pathway hitherto thought to consist of only ‘bona fide’ signaling molecules. Simoncini et al. show that estrogen exerts vascular protection following ischemia and reperfusion injury by activating PI3K and eNOS. Most striking is their finding that, in the presence of estrogen, immunoprecipitates of the estrogen receptor (ER) contain the PI3K regulatory subunit p85 and PI3K activity. Both groups show that estrogen stimulation leads to AKT activation in a PI3K-dependent manner, and evidence from Hisamoto and colleagues indicates that AKT activation is mediated by only ER-α, suggesting that the different ER family members participate in separate physiological events. Magnifying the significance of these studies is the finding that PI3K activity is not just found in estrogen receptor
immunoprecipitates but also in precipitates of the thyroid and glucocorticoid receptors1. This suggests that PI3K, which already has been implicated in practically every signaling pathway imaginable, also plays a part in the rapid and transcription-independent effects of several steroid hormones and might be an important target for designing therapies for atherosclerosis. 1 Simocini,T. et al. (2000) Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH-kinase. Nature 407, 538–541 2 Hisamoto, K. et al. Estrogen induces the Aktdependent activation of endothelial nitric oxide synthase in vascular endothelial cells. J. Biol. Chem. (in press)
Kirsten Sadler [email protected]
Letters to Trends in Cell Biology Trends in Cell Biology welcomes your correspondence about articles published in the journal or any topic of general interest to cell biologists. Please take the opportunity to air your views! Letters should be as concise as possible and no more than 700 words long, with up to one figure and 10 references. They can be sent by e-mail to: [email protected] and will be published at the discretion of the Editor.