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1.
Oncogene ; 35(8): 977-89, 2016 Feb 25.
Article in English | MEDLINE | ID: mdl-25961931

ABSTRACT

Many drugs currently used in chemotherapy work by hindering the process of ribosome biogenesis. In tumors with functional p53, the inhibition of ribosome biogenesis may contribute to the efficacy of this treatment by inducing p53 stabilization. As the level of stabilized p53 is critical for the induction of cytotoxic effects, it seems useful to highlight those cancer cell characteristics that can predict the degree of p53 stabilization following the treatment with inhibitors of ribosome biogenesis. In the present study we exposed a series of p53 wild-type human cancer cell lines to drugs such as actinomycin D (ActD), doxorubicin, 5-fluorouracil and CX-5461, which hinder ribosomal RNA (rRNA) synthesis. We found that the amount of stabilized p53 was directly related to the level of ribosome biogenesis in cells before the drug treatment. This was due to different levels of inactivation of the ribosomal proteins-MDM2 pathway of p53 digestion. Inhibition of rRNA synthesis always caused cell cycle arrest, independent of the ribosome biogenesis rate of the cells, whereas apoptosis occurred only in cells with a high rDNA transcription rate. The level of p53 stabilization induced by drugs acting in different ways from the inhibition of ribosome biogenesis, such as hydroxyurea (HU) and nutlin-3, was independent of the level of ribosome biogenesis in cells and always lower than that occurring after the inhibition of rRNA synthesis. Interestingly, in cells with a low ribosome biogenesis rate, the combined treatment with ActD and HU exerted an additive effect on p53 stabilization. These results indicated that (i) drugs inhibiting ribosome biogenesis may be highly effective in p53 wild-type cancers with a high ribosome biogenesis rate, as they induce apoptotic cell death, and (ii) the combination of drugs capable of stabilizing p53 through different mechanisms may be useful for treating cancers with a low ribosome biogenesis rate.


Subject(s)
Antineoplastic Agents/pharmacology , Organelle Biogenesis , RNA, Ribosomal/drug effects , Ribosomes/drug effects , Tumor Suppressor Protein p53/metabolism , Apoptosis , Humans , Protein Stability/drug effects , RNA, Ribosomal/biosynthesis , Ribosomes/metabolism , Transcription, Genetic/drug effects , Tumor Cells, Cultured
2.
Hum Biol ; 69(5): 653-62, 1997 Oct.
Article in English | MEDLINE | ID: mdl-9299885

ABSTRACT

The defect causing Huntington's disease (HD) has recently been discovered as an expanded CAG trinucleotide repeat located at the 5' end of the IT15 gene. This discovery allows the molecular diagnosis of HD by measuring the CAG repeat length. The normal and pathological repeat ranges in a population need to be established before a diagnostic test for HD can be performed. To determine the distribution of IT15 alleles in a population from Calabria (southern Italy), we analyzed 102 normal subjects and 9 HD patients coming from a defined area of Calabria (province of Cosenza). Expanded alleles ranged from 44 to 76 repeats. Normal alleles varied from 8 to 27 repeats, which is one of the lowest values observed at the top of the normal range; the mean was significantly different from the value observed in six other populations. The allele distribution seemed to group mainly around the mode, and no intermediate alleles were present in our sample. These results suggest a particular stability of the CAG repeat at the IT15 locus in the Calabrian group and confirm once again the peculiar genetic structure of this population.


Subject(s)
Huntington Disease/genetics , Trinucleotide Repeats/genetics , Alleles , Base Sequence , DNA/analysis , Diagnosis, Differential , Female , Genetic Markers , Humans , Huntington Disease/diagnosis , Italy , Male , Molecular Sequence Data , Polymerase Chain Reaction , Rural Population , Sensitivity and Specificity
3.
Hum Hered ; 47(1): 47-51, 1997.
Article in English | MEDLINE | ID: mdl-9017980

ABSTRACT

Spinocerebellar ataxia type 1 is caused by the expansion of a CAG trinucleotide repeat, located at the 5' end of the gene responsible for the disease (SCA1 gene). We propose a simple and rapid method for SCA1 diagnosis, avoiding both radioactive and Southern blotting analysis. The method allows an accurate allele sizing by visualization of polymerase chain reaction products through a silver nitrate-stained polyacrylamide gel.


Subject(s)
Spinocerebellar Degenerations/genetics , Trinucleotide Repeats/genetics , DNA Restriction Enzymes , Electrophoresis, Agar Gel , Genetic Markers , Humans
4.
Clin Chem ; 42(10): 1601-3, 1996 Oct.
Article in English | MEDLINE | ID: mdl-8855141

ABSTRACT

Huntington disease (HD) is a neurodegenerative disorder caused by an expanded trinucleotide repeat (CAG)n located at the 5' end of the novel IT15 gene. Discovery of this expansion allows the molecular diagnosis of HD by measuring repeat length. We applied a simple nonisotopic method to detect (CAG)n repeats, avoiding both radioactive and Southern transfer analysis. The assay is based on direct visualization of electrophoresed PCR products, after silver nitrate gel staining. Its accurate sizing of HD alleles allows presymptomatic diagnosis of at-risk persons. By avoiding isotopic manipulations, the method is safe and accurate, with no radioactive background bands. Furthermore, because it permits direct allele visualization after gel staining, the method is simple and rapid, allowing allele sizing within hours rather than days.


Subject(s)
Huntington Disease/genetics , Mutation , Polymerase Chain Reaction/methods , Proteins/genetics , Repetitive Sequences, Nucleic Acid , Alleles , DNA Primers , Humans , Huntingtin Protein , Huntington Disease/diagnosis , Nerve Tissue Proteins , Nuclear Proteins , Silver Nitrate , Staining and Labeling
5.
Gen Comp Endocrinol ; 85(1): 1-7, 1992 Jan.
Article in English | MEDLINE | ID: mdl-1532946

ABSTRACT

Progesterone (P), 17-OH-progesterone (17-OH-P), androstenedione (A), dehydroepiandrosterone (DHEA), testosterone (T), 5 alpha-dihydrotestosterone (5 alpha-DHT), and 17 beta-estradiol (E2) were measured by RIA in plasma and testes of 114 males of the oviparous lizard Podarcis s. sicula raf, a species that displays annual hibernating cycles. Hormones were determined each month from January until December, except for August. Testosterone peaked at 174.8 ng/ml of plasma after emergence (March), while 5 alpha-DHT and A peaked in April. Plasma DHEA increased during hibernation. During the refractory period there were progressive increases in P and E2 plasma levels. The testicular peak of T, in March, coincided with that observed in plasma. The striking increases in testicular T and A in early July occurred at a time when plasma androgen concentrations were low. 5 alpha-DHT increased in April when spermatogenesis with spermiation occurred and then decreased alongside a second peak of T. There is an apparent separation of plasma and testicular androgen concentrations during the reproductive cycle.


Subject(s)
Gonadal Steroid Hormones/analysis , Lizards/physiology , Testis/metabolism , 17-alpha-Hydroxyprogesterone , Androstenedione/analysis , Animals , Dehydroepiandrosterone/analysis , Dihydrotestosterone/analysis , Estradiol/analysis , Hydroxyprogesterones/analysis , Male , Periodicity , Progesterone/analysis , Radioimmunoassay , Reproduction , Testosterone
6.
J Reprod Fertil ; 90(2): 353-60, 1990 Nov.
Article in English | MEDLINE | ID: mdl-2147447

ABSTRACT

Progesterone, 17-hydroxyprogesterone, androstenedione, 5 alpha-dihydrotestosterone, dehydroepiandrosterone, testosterone and oestradiol concentrations in the plasma were measured by simultaneous radioimmunoassay in males of the lizard Podarcis s. sicula. Hormonal determinations were performed at monthly intervals from January to December (except for August). Testosterone and androstenedione reached peak values of 174.8 ng/ml and 21.4 ng/ml in the mating season (spring) and then testosterone fell abruptly to 5.9 ng/ml in June remaining at this level during hibernation when dehydroepiandrosterone (DHA) reached a maximal level of 28.5 +/- 9.3 ng/ml. Castration resulted in a marked decrease of testosterone, androstenedione, dihydrotestosterone and DHA values, with DHA being significantly lowered only during the winter season. In castrated animals, however, testosterone and androstenedione persisted conspicuously in the plasma during the breeding period, suggesting that adrenal sex steroid output may change during the annual reproductive cycle. In intact animals, progesterone and oestradiol exhibited peak values during the refractory period after the mating season. We suggest a probable role of oestradiol in the induction of the refractory period in this lizard.


Subject(s)
Gonadal Steroid Hormones/blood , Lizards/blood , Reproduction/physiology , 17-alpha-Hydroxyprogesterone , Androstenedione/blood , Animals , Dehydroepiandrosterone/blood , Dihydrotestosterone/blood , Estradiol/blood , Hibernation/physiology , Hydroxyprogesterones/blood , Male , Orchiectomy , Progesterone/blood , Seasons , Testosterone/blood
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