p53 represses the transcription of snRNA genes by preventing the formation of little elongation complex

Anwar, Delnur; Takahashi, Hidehisa; Watanabe, Masashi; Suzuki, Masanobu; Fukuda, Satoshi; Hatakeyama, Susumi

doi:10.1016/j.bbagrm.2016.06.001

Cited by 4 publications

(3 citation statements)

References 36 publications

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“…Alternatively, the LEC may be involved in transcription of other classes of genes, for which ZC3H8 may play a more central role. Recently, p53 was demonstrated to disrupt the formation of the LEC by interaction with the ELL subunit, displacing it from interaction with ICE1 and leading to inhibition of expression of some snRNAs [ 47 ]. This interaction was also predicted to displace ZC3H8.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the oncogenic phenotype by the nuclear body protein ZC3H8

Schmidt¹,

Danielson²,

Duffner³

et al. 2018

BMC Cancer

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BackgroundThe Zc3h8 gene encodes a protein with three zinc finger motifs in the C-terminal region. The protein has been identified as a component of the Little Elongation Complex, involved in transcription of small nuclear RNAs. ZC3H8 is overexpressed in a number of human and mouse breast cancer cell lines, and elevated mRNA levels are associated with a poorer prognosis for women with breast cancer.MethodsWe used RNA silencing to decrease levels of expression in mouse mammary tumor cells and overexpression of ZC3H8 in cells derived from the normal mouse mammary gland. We measured characteristics of cell behavior in vitro, including proliferation, migration, invasion, growth in soft agar, and spheroid growth. We assessed the ability of these cells to form tumors in syngeneic BALB/c mice. ZC3H8 protein was visualized in cells using confocal microscopy.ResultsTumor cells with lower ZC3H8 expression exhibited decreased proliferation rates, slower migration, reduced ability to invade through a basement membrane, and decreased anchorage independent growth in vitro. Cells with lower ZC3H8 levels formed fewer and smaller tumors in animals. Overexpression of ZC3H8 in non-tumorigenic COMMA-D cells led to an opposite effect. ZC3H8 protein localized to both PML bodies and Cajal bodies within the nucleus. ZC3H8 has a casein kinase 2 (CK2) phosphorylation site near the N-terminus, and a CK2 inhibitor caused the numerous PML bodies and ZC3H8 to coalesce to a few larger bodies. Removal of the inhibitor restored PML bodies to their original state. A mutant ZC3H8 lacking the predicted CK2 phosphorylation site showed localization and numbers of ZC3H8/PML bodies similar to wild type. In contrast, a mutant constructed with a glutamic acid in place of the phosphorylatable threonine showed dramatically increased numbers of smaller nuclear foci.ConclusionsThese experiments demonstrate that Zc3h8 expression contributes to aggressive tumor cell behavior in vitro and in vivo. Our studies show that ZC3H8 integrity is key to maintenance of PML bodies. The work provides a link between the Little Elongation Complex, PML bodies, and the cancer cell phenotype.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4674-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Regulation of the oncogenic phenotype by the nuclear body protein ZC3H8

Schmidt¹,

Danielson²,

Duffner³

et al. 2018

BMC Cancer

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“…It has also been reported that p53 represses the transcription of snRNA genes (67) and does so by preventing the little elongation complex from forming (68). It has been suggested that p53 dissociates ELL1 from the little elongation complex.…”

Section: Other Changes Associated With Stress That Could Change Snrnamentioning

confidence: 96%

Linking Endoplasmic Reticular Stress and Alternative Splicing

Carew

Nelson

Liang

et al. 2018

Preprint

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Endo-reticular stress induces the unfolded protein response including a highly conserved set of genes crucial for cell survival against a variety of onslaughts. Among the activated stress response genes is Ire1, which undergoes auto-phosphorylation and acquires a regulated Ire1-dependent mRNA decay activity. Ire1P non-canonically splices the mRNA for Xbp1 in the cytoplasm. This spliced Xbp1 serves as mRNA encoding a transcription factor for unfolded protein response genes. Meanwhile the mRNA decay function of Ire1P degrades other cellular mRNAs and can cause changes to the translation machinery by altering regulators in a cell specific manner. Naïve splenic B cells differentiate into Antibody Secreting Cells and activate Ire1 phosphorylation early on after LPS stimulation, within 18 hrs. When Ire1 is activated in B cells, in addition to Xbp1 splicing, there are large-scale changes in mRNA; inhibition of the mRNA degradation function of Ire1 both reduces the number and changes the type of genes involved in altered splicing patterns, including factors for snRNA transcription. Some of the splicing changes seen at 18 hrs after LPS persist into the late stages of antibody secretion, up to 72 hrs, while others are supplanted by new splicing changes introduced by the induction of ELL2, a transcription elongation factor. ELL2 changes mRNA processing patterns and is necessary for Immunoglobulin secretion. RNA splicing patterns in antibody secreting cells are thus shaped by endo-reticular stress, ELL2 induction, and are associated with changes in the levels of snRNAs.

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“…It has also been reported that p53 represses the transcription of snRNA genes [77] and does so by preventing the little elongation complex from forming [78]. It has been suggested that p53 dissociates ELL1 from the little elongation complex.…”

Section: Other Changes Associated With Stress That Could Change Snmentioning

confidence: 99%

Linking Endoplasmic Reticular Stress and Alternative Splicing

Carew

Nelson

Liang

et al. 2018

IJMS

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RNA splicing patterns in antibody-secreting cells are shaped by endoplasmic reticulum stress, ELL2 (eleven-nineteen lysine-rich leukemia gene 2) induction, and changes in the levels of snRNAs. Endoplasmic reticulum stress induces the unfolded protein response comprising a highly conserved set of genes crucial for cell survival; among these is Ire1, whose auto-phosphorylation drives it to acquire a regulated mRNA decay activity. The mRNA-modifying function of phosphorylated Ire1 non-canonically splices Xbp1 mRNA and yet degrades other cellular mRNAs with related motifs. Naïve splenic B cells will activate Ire1 phosphorylation early on after lipopolysaccharide (LPS) stimulation, within 18 h; large-scale changes in mRNA content and splicing patterns result. Inhibition of the mRNA-degradation function of Ire1 is correlated with further differences in the splicing patterns and a reduction in the mRNA factors for snRNA transcription. Some of the >4000 splicing changes seen at 18 h after LPS stimulation persist into the late stages of antibody secretion, up to 72 h. Meanwhile some early splicing changes are supplanted by new splicing changes introduced by the up-regulation of ELL2, a transcription elongation factor. ELL2 is necessary for immunoglobulin secretion and does this by changing mRNA processing patterns of immunoglobulin heavy chain and >5000 other genes.

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p53 represses the transcription of snRNA genes by preventing the formation of little elongation complex

Abstract: The regulation of transcription by RNA polymerase II (Pol II) is important for a variety of cellular functions. ELL/EAF-containing little elongation complex (LEC) was found to be required for transcription of Pol II-dependent small nuclear RNA (snRNA) genes.

Cited by 4 publications

References 36 publications

Regulation of the oncogenic phenotype by the nuclear body protein ZC3H8

Regulation of the oncogenic phenotype by the nuclear body protein ZC3H8

Linking Endoplasmic Reticular Stress and Alternative Splicing

Linking Endoplasmic Reticular Stress and Alternative Splicing

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