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  • apoptosis  (2)
  • Missense mutations  (1)
  • CELLS
  • 1995-1999  (3)
  • 1
    ISSN: 1432-1076
    Keywords: Galactosaemia ; Galactose-1-phosphate uridyltransferase gene ; Missense mutations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Classical galactosaemia caused by deficiency of galactose-1-phosphate uridyltransferase (GALT) is characterized by acute symptoms of hepatocellular dysfunction, sepsis, cataracts and failure to thrive. Galactose limitation reverses these complications immediately, however, most of these children have a long-term complication of verbal dyspraxia, mental retardation and ovarian failure. The GALT gene was cloned and several mutations including the common Q188R have been reported. In this study the coding region of GALT was amplified by polymerase chain reaction from genomic DNA of classical galactosaemic individuals and characterized by direct sequencing of the products. Three missense mutations were identified in three patients with a mild galactosaemic variant: (1) replacement of threonine-138 by methionine (T138M); (2) replacement of arginine by tryptophan (R259W); and (3) replacement of threonine by alanine (T350A). All three galactosaemic individuals, one girl and two boys, have varying degrees of residual GALT activity in RBC and their galactose-1-phosphate levels decreased much faster than in other galactosaemic patients. These misense mutations occur in regions that are not highly conserved domains. Conclusion The study of the molecular basis related to the phenotype variation may indeed help to prognosticate the outcome of patients with classical galactosaemia.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1573-4919
    Keywords: antisense oligonucleotide ; apoptosis ; cAMP-dependent protein kinase ; cancer cells ; growth inhibition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract The enhanced expression of the RIα subunit of cyclic AMP-dependent protein kinase type 1 (PKA-I) has been correlated with cancer cell growth. We have investigated the effects of sequence-specific inhibition of RIα gene expression on the growth of MCF-7 human breast cancer cells. We report that RIα antisense treatment results in a reduction in RIα expression at both mRNA and protein levels and inhibition of cell growth. The growth inhibition was accompanied by changes in cell morphology, cleavage of poly(ADP-ribose) polymerase (PARP) and appearance of apoptotic nuclei. In addition, bcl-2 protein level was reduced and p53 expression increased in growth arrested cells. Interestingly, RIα antisense inhibited cell viability and induced apoptosis in the absence of p53, suggesting that these actions of RIα antisense are exerted independent of p53. In contrast, two- and four-base mismatched control oligonucleotides had no effect on either cell growth or morphology. These results demonstrate that the RIα antisense, which efficiently depletes the growth stimulatory molecule RIα, induces cell differentiation and apoptosis, providing a new approach to combat breast cancer cell growth.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1573-7217
    Keywords: antisense ; protein kinase A ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In recent years, several laboratories have explored the possibility of using antisense oligodeoxynucleotides for specific manipulation of gene expression leading to cancer treatment. The enhanced expression of the RIα subunit of cyclic AMP-dependent protein kinase type I (PKA-I) has been correlated with cancer cell growth. In the present study, the effects of an antisense oligodeoxynucleotide targeted against RIα subunit of PKA-I on growth inhibition and apoptosis in MDA-MB-231 human breast cancer cells were investigated. The growth inhibitory effects of RIα antisense oligodeoxynucleotide correlated with a decrease in the RIα mRNA and protein levels. The growth inhibition was accompanied by changes in the cell cycle phase distribution, cell morpbology, cleavage of poly (ADP-ribose) polymerase (PARP), and appearance of apoptotic nuclei. By comparison, mismatched control oligodeoxynucleotide had no effect. On the basis of these results, it can be suggested that the RIα antisense oligodeoxynucleotide, which efficiently depletes the growth stimulatory RIα and induces apoptosis/differentiation, could be used as a therapeutic agent for breast cancer treatment.
    Type of Medium: Electronic Resource
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