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Regulation of gene expression by the anticonvulsant VPA suggests potential new uses
10
News & Comment
transcription factor cAMP response element-binding protein (CREB) is the main promoter of survival in the presynaptic neurons. CREB phosphorylation by ERK5 at Ser133 is mediated by mitogen-stimulated ribosomal S6 kinase (RSK). During retrograde signaling, this step appears to be crucial for developing neurons. The unique biological function of ERK5 might be
TRENDS in Pharmacological Sciences Vol.23 No.1 January 2002
conferred by several distinctive features of this kinase related to its size, which is different from ERK1/2, or by different upstream and downstream events that are part of its signaling pathway. The involvement of ERK1/2 in neuronal death and/or survival following ischemia or neurodegeneration is controversial. Perhaps the ERK5 cascade discussed here is
a more likely candidate for neuroprotection in vivo. 1 Watson, F.L. et al. (2001) Neurotrophins use the Erk5 pathway to mediate a retrograde survival response. Nat. Neurosci. 4, 981–988
Madalina Stanciu [email protected]
Regulation of gene expression by the anticonvulsant VPA suggests potential new uses Although some drugs are used widely to treat certain disorders, their mechanism of action is unknown. One such drug is valproic acid (VPA), which was serendipitously discovered to possess anticonvulsant and mood-stabilizing properties during its use as a solvent for other compounds. Despite several hypotheses being proposed for a mechanism of action of VPA, the direct targets of this compound have not been identified. Now Phiel et al. [1] have shown that histone deacetylase (HDAC), an enzyme involved in the repression of gene expression, is one target of VPA. The authors compare the actions of VPA to those of lithium, a compound that exhibits similar anticonvulsant and mood-stabilizing properties. The actions of both compounds are delayed, which has been suggested to be due to changes in gene expression. Indeed, lithium is known to increase the levels of β-catenin, which results in activation of Wnt-dependent genes. Using a reporter gene assay, Phiel and colleagues show that VPA can also activate Wntdependent gene expression. Activation of
this reporter by VPA and lithium is synergistic, which demonstrates that although these compounds produce the same effect they must act through different mechanisms. In addition to Wnt-dependent gene activation, VPA appeared to increase gene expression more generally. VPA, like lithium, increased the levels of β-catenin, although, unlike lithium, which causes an increase in β-catenin protein stability, VPA increased levels of β-catenin mRNA. Because of the more general effect of VPA on gene expression, Phiel et al. reasoned that VPA might inhibit HDAC activity, and documented three lines of evidence supporting this hypothesis: (1) VPA inhibits HDAC activity in vitro at concentrations within the therapeutic range in humans; (2) treatment of cells with VPA results in hyperacetylation of histone H4 in a similar manner to that observed by another known HDAC inhibitor, trichostatin A (TSA); and (3) overexpression of HDAC antagonizes gene activation by VPA. VPA is also known to be a potent teratogen and can result in spina bifida and neural tube defects in humans and rodents.
Both VPA and TSA were shown by Phiel and colleagues to produce similar defects in the development of Xenopus embryos. Analogues of VPA that had previously been shown to possess anticonvulsant activity did not produce developmental defects and did not inhibit HDAC activity in vitro. These results suggest that the teratogenic properties of VPA involve HDAC inhibition but the anticonvulsant properties of VPA might not. These experiments also demonstrate that VPA must have multiple mechanisms of action. Because inhibitors of HDAC activity have therapeutic potential in the treatment of leukaemia, neuroblastomas and some carcinomas, the authors suggest that VPA, being a relatively safe, well tested drug, could prove an attractive alternative to TSA.
hormone. City of Hope claimed that Genentech licensed the technology covered in the patent to pharmaceutical companies without paying royalties. Genentech lawyers countered that the royalties were due only if City of Hope scientists helped develop the gene for a specific bioengineered protein. City of Hope’s general counsel has announced that the hospital will retry the breach-of contract case. The retrial date has been set for January 2002. AB
Drug therapy for polyglutamine diseases?
1 Phiel, C.J. et al. (2001) Histone deacetylase is a direct target of vaproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J. Biol. Chem. 276, 36734–36741
Ian C. Wood [email protected]
In Brief
Genentech lawsuit ends in mistrial A two-year-old lawsuit filed by City of Hope National Medical Center against Genentech ended in a mistrial on 15 October 2001 because the jury declared itself unable to reach a decision. At the core of the conflict was a 25-year-old contract relating to bioengineered human insulin and growth http://tips.trends.com
Huntington’s disease, a progressive neurodegenerative disorder, is caused by the expansion of a polyglutamine repeat region on the huntingtin protein. Because this expansion is genetically determined, most research has focused on genetic approaches. However, a recent study now
0165-6147/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.
News & Comment
transcription factor cAMP response element-binding protein (CREB) is the main promoter of survival in the presynaptic neurons. CREB phosphorylation by ERK5 at Ser133 is mediated by mitogen-stimulated ribosomal S6 kinase (RSK). During retrograde signaling, this step appears to be crucial for developing neurons. The unique biological function of ERK5 might be
TRENDS in Pharmacological Sciences Vol.23 No.1 January 2002
conferred by several distinctive features of this kinase related to its size, which is different from ERK1/2, or by different upstream and downstream events that are part of its signaling pathway. The involvement of ERK1/2 in neuronal death and/or survival following ischemia or neurodegeneration is controversial. Perhaps the ERK5 cascade discussed here is
a more likely candidate for neuroprotection in vivo. 1 Watson, F.L. et al. (2001) Neurotrophins use the Erk5 pathway to mediate a retrograde survival response. Nat. Neurosci. 4, 981–988
Madalina Stanciu [email protected]
Regulation of gene expression by the anticonvulsant VPA suggests potential new uses Although some drugs are used widely to treat certain disorders, their mechanism of action is unknown. One such drug is valproic acid (VPA), which was serendipitously discovered to possess anticonvulsant and mood-stabilizing properties during its use as a solvent for other compounds. Despite several hypotheses being proposed for a mechanism of action of VPA, the direct targets of this compound have not been identified. Now Phiel et al. [1] have shown that histone deacetylase (HDAC), an enzyme involved in the repression of gene expression, is one target of VPA. The authors compare the actions of VPA to those of lithium, a compound that exhibits similar anticonvulsant and mood-stabilizing properties. The actions of both compounds are delayed, which has been suggested to be due to changes in gene expression. Indeed, lithium is known to increase the levels of β-catenin, which results in activation of Wnt-dependent genes. Using a reporter gene assay, Phiel and colleagues show that VPA can also activate Wntdependent gene expression. Activation of
this reporter by VPA and lithium is synergistic, which demonstrates that although these compounds produce the same effect they must act through different mechanisms. In addition to Wnt-dependent gene activation, VPA appeared to increase gene expression more generally. VPA, like lithium, increased the levels of β-catenin, although, unlike lithium, which causes an increase in β-catenin protein stability, VPA increased levels of β-catenin mRNA. Because of the more general effect of VPA on gene expression, Phiel et al. reasoned that VPA might inhibit HDAC activity, and documented three lines of evidence supporting this hypothesis: (1) VPA inhibits HDAC activity in vitro at concentrations within the therapeutic range in humans; (2) treatment of cells with VPA results in hyperacetylation of histone H4 in a similar manner to that observed by another known HDAC inhibitor, trichostatin A (TSA); and (3) overexpression of HDAC antagonizes gene activation by VPA. VPA is also known to be a potent teratogen and can result in spina bifida and neural tube defects in humans and rodents.
Both VPA and TSA were shown by Phiel and colleagues to produce similar defects in the development of Xenopus embryos. Analogues of VPA that had previously been shown to possess anticonvulsant activity did not produce developmental defects and did not inhibit HDAC activity in vitro. These results suggest that the teratogenic properties of VPA involve HDAC inhibition but the anticonvulsant properties of VPA might not. These experiments also demonstrate that VPA must have multiple mechanisms of action. Because inhibitors of HDAC activity have therapeutic potential in the treatment of leukaemia, neuroblastomas and some carcinomas, the authors suggest that VPA, being a relatively safe, well tested drug, could prove an attractive alternative to TSA.
hormone. City of Hope claimed that Genentech licensed the technology covered in the patent to pharmaceutical companies without paying royalties. Genentech lawyers countered that the royalties were due only if City of Hope scientists helped develop the gene for a specific bioengineered protein. City of Hope’s general counsel has announced that the hospital will retry the breach-of contract case. The retrial date has been set for January 2002. AB
Drug therapy for polyglutamine diseases?
1 Phiel, C.J. et al. (2001) Histone deacetylase is a direct target of vaproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J. Biol. Chem. 276, 36734–36741
Ian C. Wood [email protected]
In Brief
Genentech lawsuit ends in mistrial A two-year-old lawsuit filed by City of Hope National Medical Center against Genentech ended in a mistrial on 15 October 2001 because the jury declared itself unable to reach a decision. At the core of the conflict was a 25-year-old contract relating to bioengineered human insulin and growth http://tips.trends.com
Huntington’s disease, a progressive neurodegenerative disorder, is caused by the expansion of a polyglutamine repeat region on the huntingtin protein. Because this expansion is genetically determined, most research has focused on genetic approaches. However, a recent study now
0165-6147/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.