Downregulation of SUN2, a novel tumor suppressor, mediates miR-221/222-induced malignancy in central nervous system embryonal tumors.

Embryonal tumors of the central nervous system represent a highly malignant tumor group of medulloblastoma (MB), atypical teratoid/rhabdoid tumor (AT/RT) and primitive neuroectodermal tumor that frequently afflict children. AT/RT is often misdiagnosed as MB/primitive neuroectodermal tumor but with higher recurrence and lower survival rates. Pathogenesis of AT/RT is largely unknown. In this study, we report both the miRNome and transcriptome traits in AT/RT and MB by using small RNA sequencing and gene expression microarray analyses. Our findings demonstrate that the miR-221/222-encoded micro RNAs are abundantly expressed in AT/RT but not in MB, which contribute substantially to the malignancy of embryonal tumors. miR-221/222 targeted SUN2, a newly discovered tumor suppressor, directly to increase cell proliferation and tumor malignancy in vitro and in vivo. Immunohistochemistry against SUN2 in a tissue microarray of 33 AT/RT and 154 MB tumor specimens also detected less SUN2 protein in AT/RT. Collectively, this study uncovers a novel tumor suppressor, SUN2, plays a critical role in miR-221/222-mediated AT/RT malignancy as well as supports miR-221/222 and SUN2 represent new promising targets for more active therapies in AT/RT. In addition, our miRNome and transcriptome data also provide a roadmap for further embryonal tumor research.

Treacle recruits RNA polymerase I complex to the nucleolus that is independent of UBF.

Mutations in treacle lead to Treacher Collins syndrome (TCS), an autosomal dominant disorder of craniofacial development. Treacle associates with upstream binding factor (UBF) to regulate rRNA gene (rDNA) transcription, but the precise mechanisms mediated by treacle remain elusive. Here we show that the central repeated domain of treacle binds with RNA polymerase I (Pol I), while that the treacle C-terminus is involved in rDNA promoter recognition and UBF recruitment. Knockdown of treacle resulted in dispersion of Pol I and UBF away from nucleolus, whereas interactions of treacle with Pol I and rDNA promoter were not disrupted by UBF depletion. These findings indicate that treacle, but not UBF, is essential for nucleolar recruitment of Pol I transcription complex. Furthermore, C-terminally truncated treacle, mimicking TCS-associated mutations, failed to target to the nucleolus, possibly causing loss-of-function in the mutant treacle. Our observations support that TCS results from haploinsufficiency of treacle.

Chromatin tethering effects of hNopp140 are involved in the spatial organization of nucleolus and the rRNA gene transcription.

The short arms of five human acrocentric chromosomes contain ribosomal gene (rDNA) clusters where numerous mini-nucleoli arise at the exit of mitosis. These small nucleoli tend to coalesce into one or a few large nucleoli during interphase by unknown mechanisms. Here, we demonstrate that the N- and C-terminal domains of a nucleolar protein, hNopp140, bound respectively to alpha-satellite arrays and rDNA clusters of acrocentric chromosomes for nucleolar formation. The central acidic-and-basic repeated domain of hNopp140, possessing a weak self-self interacting ability, was indispensable for hNopp140 to build up a nucleolar round-shaped structure. The N- or the C-terminally truncated hNopp140 caused nucleolar segregation and was able to alter locations of the rDNA transcription, as mediated by detaching the rDNA repeats from the acrocentric alpha-satellite arrays. Interestingly, an hNopp140 mutant, made by joining the N- and C-terminal domains but excluding the entire central repeated region, induced nucleolar disruption and global chromatin condensation. Furthermore, RNAi knockdown of hNopp140 resulted in dispersion of the rDNA and acrocentric alpha-satellite sequences away from nucleolus that was accompanied by rDNA transcriptional silence. Our findings indicate that hNopp140, a scaffold protein, is involved in the nucleolar assembly, fusion, and maintenance.

Heterogeneity of propagation of excitation in epicardium of pulmonary veins ostia in rabbit during cooling.

OBJECTIVE: The purpose of this research was to study the propagation of the excitation wave along epicardium in the area of the pulmonary veins ostia in rabbit in normal conditions and while cooling. METHODS: The excitation wave spreading along epicardium in the area of pulmonary veins ostia in the left atrium at 36-37 degrees C and when cooling to 32 degrees C was studied by the method of electrocardiochronotopography in rabbit of Chinchilla species, five months age. The size of the registering surface of the electrode was 1.08 x 1.08 cm. RESULTS: The time of depolarization when cooling from 36 degrees C to 32 degrees C changes unevenly in various zones of pulmonary veins. On the epicardium of pulmonary veins area at temperature reduction from 36 degrees C to 33 degrees C, change in the direction of excitation and essential reduction of depolarization time, and its significant increase under further cooling to 32 degrees C were observed. In the middle part of the left atrium at temperature reduction, change in the main direction of the excitation wave propagation, shift of the location of the areas of the latest depolarization were revealed and the front become more homogeneous. CONCLUSION: In the area of the left atrium base the heterogeneity of the front of depolarization at temperature reduction was revealed.