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Involvement of DNA topoisomerase IIbeta in neuronal differentiation.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2001 Feb 23; Vol. 276 (8), pp. 5769-78. Date of Electronic Publication: 2000 Dec 05. - Publication Year :
- 2001
-
Abstract
- Two isoforms of DNA topoisomerase II (topo II) have been identified in mammalian cells. While topo IIalpha is essential for chromosome segregation in mitotic cells, in vivo function of topo IIbeta remains to be clarified. Here we demonstrate that the nucleoplasmic topo IIbeta, highly expressed in differentiating cerebellar neurons, is the catalytically competent entity operating directly on chromatin DNA in vivo. When the cells reached terminal differentiation, this in vivo activity decreased to a negligible level with concomitant loss of the nucleoplasmic enzyme. Effects of topo II-specific inhibitors were analyzed in a primary culture of cerebellar granule neurons that can mimic the in vivo situation. Only the beta isoform was expressed in granule cells differentiating in vitro. ICRF-193, a catalytic topo II inhibitor, suppressed the transcriptional induction of amphiphysin I which is essential for mature neuronal activity. The effect decreased significantly as the cells differentiate. Expression profiling with a cDNA macroarray showed that 18% of detectable transcripts were up-regulated during the differentiation and one-third of them were susceptible to ICRF-193. The results suggest that topo IIbeta is involved in an early stage of granule cell differentiation by potentiating inducible neuronal genes to become transcribable probably through alterations in higher order chromatin structure.
- Subjects :
- Animals
Animals, Newborn
Cell Differentiation
Cell Nucleus enzymology
Cerebellar Cortex enzymology
Cerebellar Cortex growth & development
DNA Topoisomerases, Type II isolation & purification
DNA-Binding Proteins isolation & purification
DNA-Binding Proteins metabolism
Diketopiperazines
Etoposide pharmacology
Gene Expression Regulation
Isoenzymes isolation & purification
Isoenzymes metabolism
Male
Nerve Tissue Proteins biosynthesis
Neurons metabolism
Piperazines pharmacology
RNA, Messenger metabolism
Rats
Rats, Wistar
Topoisomerase II Inhibitors
Cerebellar Cortex cytology
DNA Topoisomerases, Type II metabolism
Neurons cytology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 276
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 11106659
- Full Text :
- https://doi.org/10.1074/jbc.M008517200