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Cell cycle dependent phosphorylation and subnuclear organization of the histone gene regulator p220(NPAT) in human embryonic stem cells 总被引:1,自引:0,他引:1
Ghule PN Becker KA Harper JW Lian JB Stein JL van Wijnen AJ Stein GS 《Journal of cellular physiology》2007,213(1):9-17
Human embryonic stem (ES) cells have an expedited cell cycle ( approximately 15 h) due to an abbreviated G1 phase ( approximately 2.5 h) relative to somatic cells. One principal regulatory event during cell cycle progression is the G1/S phase induction of histone biosynthesis to package newly replicated DNA. In somatic cells, histone H4 gene expression is controlled by CDK2 phosphorylation of p220(NPAT) and localization of HiNF-P/p220(NPAT) complexes with histone genes at Cajal body related subnuclear foci. Here we show that this 'S point' pathway is operative in situ in human ES cells (H9 cells; NIH-designated WA09). Immunofluorescence microscopy shows an increase in p220(NPAT) foci in G1 reflecting the assembly of histone gene regulatory complexes in situ. In contrast to somatic cells where duplication of p220(NPAT) foci is evident in S phase, the increase in the number of p220(NPAT) foci in ES cells appears to precede the onset of DNA synthesis as measured by BrdU incorporation. Phosphorylation of p220(NPAT) at CDK dependent epitopes is most pronounced in S phase when cells exhibit elevated levels of cyclins E and A. Our data indicate that subnuclear organization of the HiNF-P/p220(NPAT) pathway is rapidly established as ES cells emerge from mitosis and that p220(NPAT) is subsequently phosphorylated in situ. Our findings establish that the HiNF-P/p220(NPAT) gene regulatory pathway operates in a cell cycle dependent microenvironment that supports expression of DNA replication-linked histone genes and chromatin assembly to accommodate human stem cell self-renewal. 相似文献
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HiNF-P directly links the cyclin E/CDK2/p220NPAT pathway to histone H4 gene regulation at the G1/S phase cell cycle transition
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Miele A Braastad CD Holmes WF Mitra P Medina R Xie R Zaidi SK Ye X Wei Y Harper JW van Wijnen AJ Stein JL Stein GS 《Molecular and cellular biology》2005,25(14):6140-6153
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The survival motor neurons (smn) gene in mice is essential for embryonic viability. In humans, mutation of the telomeric copy of the SMN1 gene causes spinal muscular atrophy, an autosomal recessive disease. Here we report that the SMN protein interacts with the zinc-finger protein ZPR1 and that these proteins colocalize in small subnuclear structures, including gems and Cajal bodies. SMN and ZPR1 redistribute from the cytoplasm to the nucleus in response to serum. This process is disrupted in cells from patients with Werdnig-Hoffman syndrome (spinal muscular atrophy type I) that have SMN1 mutations. Similarly, decreased ZPR1 expression prevents SMN localization to nuclear bodies. Our data show that ZPR1 is required for the localization of SMN in nuclear bodies. 相似文献
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