TY - JOUR
T1 - Involvement of DNA Topoisomerase IIβ in Neuronal Differentiation
AU - Tsutsui, Ken
AU - Tsutsui, Kimiko
AU - Sano, Kuniaki
AU - Kikuchi, Akihiko
AU - Tokunaga, Akira
PY - 2001/2/23
Y1 - 2001/2/23
N2 - Two isoforms of DNA topoisomerase II (topo II) have been identified in mammalian cells. While topo IIα is essential for chromosome segregation in mitotic cells, in vivo function of topo IIβ remains to be clarified. Here we demonstrate that the nucleoplasmic topo IIβ, 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 β 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 IIβ 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.
AB - Two isoforms of DNA topoisomerase II (topo II) have been identified in mammalian cells. While topo IIα is essential for chromosome segregation in mitotic cells, in vivo function of topo IIβ remains to be clarified. Here we demonstrate that the nucleoplasmic topo IIβ, 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 β 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 IIβ 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.
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U2 - 10.1074/jbc.M008517200
DO - 10.1074/jbc.M008517200
M3 - Article
C2 - 11106659
AN - SCOPUS:0035937159
VL - 276
SP - 5769
EP - 5778
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 8
ER -