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Gene associated with lupus nephritis identified
How tamoxifen induces apoptosis of c-myc may be which clinically attainable concentrations of tamoxifen induce apopotosis in oestrogenbreast(ER-) receptor-negative cancer cell-lines (YPVC7 1996; 88: 279-284). This finding could have
verexpression the by means
therapeutic implications. The observation that tamoxifen, an anti-oestrogen, has effects against
ER- breast-cancer cell-line. Shortterm
exposure
(24 h)
to
1
umol/L
tamoxifen resulted in a slight increase in c-myc protein expression and a concomitant increase in cell growth. By contrast, extended treatment with tamoxifen (72 h) induced apoptosis of the cells and a further increase in c-myc protein expression (table). The correlation between c-
myc-expression levels, growth stimulation, and apoptosis was confirmed by treating the cells with c-myc antisense oligonucleotide. The cytostatic and apoptotic effects of tamoxifen were partly reversed by the antisense oligonucleotide but not by sense oligonucleotide. These results do not yet explain how tamoxifen induces
expression. However, apoptosis is induced by a varic-myc
ER- tumours, cannot be due
binding
means
that its action
simply
to
competitive
to
oestrogen receptors. Studies in breast-cancer cell-lines have shown that tamoxifen can induce apoptosis in both oestrogenreceptor-positive and receptor-negative lines. To determine how tamoxifen induces apoptosis in ER- cells, Y Kang and colleagues looked at the effect of tamoxifen on c-myc protein expression levels in MDA-231, an
Gene associated with
818
Jane
Bradbury
lupus nephritis identified
gene associated with increased risk of lupus nephritis in African Americans has been identified by US National Institutes of Health researchers. African Americans are three times more susceptible to systemic lupus erythematosus than Americans of European descent. The researchers, led by Jane E Cornell Salmon of University Medical College, New York City, examined a gene, FcyRIla, that controls for production of Fc receptors, which help in the capture and destruction of immune complexes. The human FcyRIla gene is codominantly expressed as alleles R131 and H131. The R131 allele codes for Fc receptors poorly efficient at immune removing complexes, whereas the H131 receptors are highly efficient at doing so. A total of 257 African Americans 139 with African lupus and Americans without the disease were
A
etv of vhvsiol02ical stimuli and underlies the cytocidal actions of many therapeutic agents. Different agents probably act through different downstream signalling pathways, so combinations of therapies may well be additive in effect. An understanding of which therapeutic agent acts through which signalling pathway should allow a rational choice of therapeutic combinations.
studied in a two-stage, cross-sectional study at four US research centres. The first stage of the research, conducted on 43 African Americans with lupus and another 39 without the disease, indicated that homozygosity for FcyRIIa-R131 was commoner among the lupus patients than among controls. The second stage, done on 214 lupus patients and 100 non-lupus controls, supported the findings in the first stage. 80 (37%) of lupus patients were homozygous for FcyRlla-R131, compared with 23 (23%) of non-lupus controls. 17% of lupus patients were homozygous for FcyRIla-H131, compared with 27% among controls. A trend analysis of the genotype distribution showed a highly significant decrease in FcyRlla-H131 as the likelihood of lupus nephritis increased (J Clin Invest 1996; 97: Mark
Quinn
1348-54).
Cystatin B mutations are implicated in type of epilepsy utations in the cystatin B gene involved in an autosomal recessive inherited form of epilepsy. Progressive myoclonus epilepsy is a group of five inherited epilepsies that are characterised by myoclonic seizures, generalised epilepsy and
are
progressive neurological deterioration. Unverricht-Lundborg type epilepsy (EPM1) was previously linked
to
human
chromosome
21q22.3. L A Pennacchio and colleagues (Science 1996; 271: 1731-34) report that one of the genes lying in this region of the chromois a previously described some protein, cystatin B. To test whether this gene is implicated in EPM1, the group measured the expression of cystatin B in lymphoblastoid cells of affected and unaffected individuals. mRNA levels for cystatin B were greatly reduced in the former. The researchers then sequenced the gene from affected individuals. Two mutations were found-a 3’ splicesite mutation and a stop codon mutation. Cystatin B is a ubiquitously expressed member of the superfamily of cysteine protease inhibitors and is thought to inhibit any proteases that leak out of the lysosome. Why the loss of a protease inhibitor in all the cells of the body should cause the symptoms of EPM1, which has a clear tissue-specific phenotype, is not clear but there may be parallels with lysosomal storage diseases where deficiencies in lysosomal enzymes affect only a subset of neuronal cells. Two other types of progressive now
myoclonus epilepsies produce
Jane
similar
symp-
EPM1and may also turn out to involve members of the cystatin superfamily or their substrates. In all these diseases the identification of the affected gene should provide new molecular targets for therapy and may also help to explain the differences in drug response between different forms of epilepsy. Interestingly, another member of the cystatin family, cystatin C, is responsible for hereditary cerebral angiopathy, but in this case the disease is inherited dominantly and is characterised by deposition of the enzyme in affected brain arteries. toms
Bradbury
to
verexpression the by means
therapeutic implications. The observation that tamoxifen, an anti-oestrogen, has effects against
ER- breast-cancer cell-line. Shortterm
exposure
(24 h)
to
1
umol/L
tamoxifen resulted in a slight increase in c-myc protein expression and a concomitant increase in cell growth. By contrast, extended treatment with tamoxifen (72 h) induced apoptosis of the cells and a further increase in c-myc protein expression (table). The correlation between c-
myc-expression levels, growth stimulation, and apoptosis was confirmed by treating the cells with c-myc antisense oligonucleotide. The cytostatic and apoptotic effects of tamoxifen were partly reversed by the antisense oligonucleotide but not by sense oligonucleotide. These results do not yet explain how tamoxifen induces
expression. However, apoptosis is induced by a varic-myc
ER- tumours, cannot be due
binding
means
that its action
simply
to
competitive
to
oestrogen receptors. Studies in breast-cancer cell-lines have shown that tamoxifen can induce apoptosis in both oestrogenreceptor-positive and receptor-negative lines. To determine how tamoxifen induces apoptosis in ER- cells, Y Kang and colleagues looked at the effect of tamoxifen on c-myc protein expression levels in MDA-231, an
Gene associated with
818
Jane
Bradbury
lupus nephritis identified
gene associated with increased risk of lupus nephritis in African Americans has been identified by US National Institutes of Health researchers. African Americans are three times more susceptible to systemic lupus erythematosus than Americans of European descent. The researchers, led by Jane E Cornell Salmon of University Medical College, New York City, examined a gene, FcyRIla, that controls for production of Fc receptors, which help in the capture and destruction of immune complexes. The human FcyRIla gene is codominantly expressed as alleles R131 and H131. The R131 allele codes for Fc receptors poorly efficient at immune removing complexes, whereas the H131 receptors are highly efficient at doing so. A total of 257 African Americans 139 with African lupus and Americans without the disease were
A
etv of vhvsiol02ical stimuli and underlies the cytocidal actions of many therapeutic agents. Different agents probably act through different downstream signalling pathways, so combinations of therapies may well be additive in effect. An understanding of which therapeutic agent acts through which signalling pathway should allow a rational choice of therapeutic combinations.
studied in a two-stage, cross-sectional study at four US research centres. The first stage of the research, conducted on 43 African Americans with lupus and another 39 without the disease, indicated that homozygosity for FcyRIIa-R131 was commoner among the lupus patients than among controls. The second stage, done on 214 lupus patients and 100 non-lupus controls, supported the findings in the first stage. 80 (37%) of lupus patients were homozygous for FcyRlla-R131, compared with 23 (23%) of non-lupus controls. 17% of lupus patients were homozygous for FcyRIla-H131, compared with 27% among controls. A trend analysis of the genotype distribution showed a highly significant decrease in FcyRlla-H131 as the likelihood of lupus nephritis increased (J Clin Invest 1996; 97: Mark
Quinn
1348-54).
Cystatin B mutations are implicated in type of epilepsy utations in the cystatin B gene involved in an autosomal recessive inherited form of epilepsy. Progressive myoclonus epilepsy is a group of five inherited epilepsies that are characterised by myoclonic seizures, generalised epilepsy and
are
progressive neurological deterioration. Unverricht-Lundborg type epilepsy (EPM1) was previously linked
to
human
chromosome
21q22.3. L A Pennacchio and colleagues (Science 1996; 271: 1731-34) report that one of the genes lying in this region of the chromois a previously described some protein, cystatin B. To test whether this gene is implicated in EPM1, the group measured the expression of cystatin B in lymphoblastoid cells of affected and unaffected individuals. mRNA levels for cystatin B were greatly reduced in the former. The researchers then sequenced the gene from affected individuals. Two mutations were found-a 3’ splicesite mutation and a stop codon mutation. Cystatin B is a ubiquitously expressed member of the superfamily of cysteine protease inhibitors and is thought to inhibit any proteases that leak out of the lysosome. Why the loss of a protease inhibitor in all the cells of the body should cause the symptoms of EPM1, which has a clear tissue-specific phenotype, is not clear but there may be parallels with lysosomal storage diseases where deficiencies in lysosomal enzymes affect only a subset of neuronal cells. Two other types of progressive now
myoclonus epilepsies produce
Jane
similar
symp-
EPM1and may also turn out to involve members of the cystatin superfamily or their substrates. In all these diseases the identification of the affected gene should provide new molecular targets for therapy and may also help to explain the differences in drug response between different forms of epilepsy. Interestingly, another member of the cystatin family, cystatin C, is responsible for hereditary cerebral angiopathy, but in this case the disease is inherited dominantly and is characterised by deposition of the enzyme in affected brain arteries. toms
Bradbury
to