Phorbol esters dPPA/dPA promote furin expression involving transcription factor CEBPβ in neuronal cells

The RE1-silencing transcription factor (REST) is the major scaffold protein for assembly of neuronal gene silencing complexes that suppress gene transcription through regulating the surrounding chromatin structure. REST represses neuronal gene expression in stem cells and non-neuronal cells, but it is minimally expressed in neuronal cells to ensure proper neuronal development. Dysregulation of REST function has been implicated in several cancers and neurological diseases. Modulating REST gene silencing is challenging because cellular and developmental differences can affect its activity. We therefore considered the possibility of modulating REST activity through its regulatory proteins. The human small C-terminal domain phosphatase 1 (SCP1) regulates the phosphorylation state of REST at sites that function as REST degradation checkpoints. Using kinetic analysis and direct visualization with X-ray crystallography, we show that SCP1 dephosphorylates two degron phosphosites of REST with a clear preference for phosphoserine 861 (pSer-861). Furthermore, we show that SCP1 stabilizes REST protein levels, which sustains REST's gene silencing function in HEK293 cells. In summary, our findings strongly suggest that REST is a bona fide substrate for SCP1 in vivo and that SCP1 phosphatase activity protects REST against degradation. These observations indicate that targeting REST via its regulatory protein SCP1 can modulate its activity and alter signaling in this essential developmental pathway.

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NF-kappa B p100 (Lyt-10) is a component of H2TF1 and can function as an I kappa B-like molecule.

Molecular and Cellular Biology ◽

10.1128/mcb.13.10.6089 ◽

1993 ◽

Vol 13 (10) ◽

pp. 6089-6101 ◽

Cited By ~ 64

Author(s):

R I Scheinman ◽

A A Beg ◽

A S Baldwin

Keyword(s):

Transcription Factor ◽

Dna Binding ◽

Phorbol Esters ◽

Interleukin 1 ◽

Binding Activity ◽

Proteolytic Processing ◽

Cellular Growth ◽

Nf Kappa B ◽

Dna Binding Activity ◽

Multiple Copies

NF-kappa B is an important transcription factor regulating expression of genes involved in immune function, inflammation, and cellular growth control. NF-kappa B activity is induced by numerous stimuli, such as phorbol esters, B- and T-cell mitogens, the cytokines tumor necrosis factor and interleukin-1, and serum growth factors. The standard model for the induction of NF-kappa B activity involves the release of the transcription factor from a cytoplasmic inhibitor termed I kappa B, allowing translocation of NF-kappa B to the nucleus. I kappa B contains multiple copies of the so-called ankyrin repeat, which are apparently necessary for its function. Subunits comprising NF-kappa B and related binding activities are members of the Rel multigene family. Two such subunits, p50 and p52 (also called p50B), are proteolytically processed from precursors of 105 kDa (also called p105 and NFKB1) and 100 kDa (also called p100, NFKB2, and Lyt-10), respectively. Both contain N-terminal Rel-homologous domains as well as multiple copies of C-terminal ankyrin repeats. We show here that NF-kappa B p100 is a component of the previously identified DNA-binding activity H2TF1. In addition, we show that p100 is localized in the cytoplasm in HeLa cells, where it is associated with c-Rel, p50, or p65 (RelA). In transient-transfection assays, p100 represses the ability of NF-kappa B p65 to activate a kappa B-containing reporter construct. Transfection of p100 also results in a loss of nuclear p65 DNA binding to a kappa B probe, as measured by an electrophoretic mobility shift assay, and a loss of nuclear p65 immunoreactivity, as measured by immunoblotting. This loss of nuclear p65 is paralleled by a gain of p65 DNA-binding activity and immunoreactivity in the cytoplasm. We interpret these data as demonstrating that p100 functions as an I kappa B-like molecule to sequester Rel family members in the cytoplasm. Proteolytic processing of p100 to the activator p52 is predicted to generate several new forms of Rel family heterodimers and therefore represents a form of regulation of NF-kappa B activity distinct from the classic I kappa B pathway.

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GSK-3β down-regulates the transcription factor Nrf2 after oxidant damage: relevance to exposure of neuronal cells to oxidative stress

Journal of Neurochemistry ◽

10.1111/j.1471-4159.2007.05124.x ◽

2008 ◽

Vol 105 (1) ◽

pp. 192-202 ◽

Cited By ~ 139

Author(s):

Ana I. Rojo ◽

María Rosa de Sagarra ◽

Antonio Cuadrado

Keyword(s):

Oxidative Stress ◽

Transcription Factor ◽

Neuronal Cells ◽

Oxidant Damage ◽

Gsk 3Β

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Functional interaction between different isoforms of the Oct-2 transcription factor expressed in neuronal cells

Biochemical Journal ◽

10.1042/bj2980245 ◽

1994 ◽

Vol 298 (1) ◽

pp. 245-248 ◽

Cited By ~ 6

Author(s):

K A Lillycrop ◽

J K Estridge ◽

D S Latchman

Keyword(s):

Transcription Factor ◽

B Lymphocyte ◽

Specific Activity ◽

Neuronal Cells ◽

Cell Types ◽

Immediate Early ◽

Early Promoter ◽

Cell Type Specific ◽

Simplex Virus

The predominant neuronal isoforms of the Oct-2 transcription factor, Oct 2.4 and Oct 2.5, repress the herpes simplex virus immediate-early promoter both in neuronal cells and in fibroblasts normally lacking Oct-2. In contrast, the predominant B lymphocyte form Oct 2.1, which is present at a lower level in neuronal cells, activates the immediate-early promoter in fibroblasts but represses it in neuronal cells. We show here that both Oct 2.4 and Oct 2.5 can functionally interact with Oct 2.1 and convert it from an activator into a repressor. Hence, the cell type-specific activity of Oct 2.1 results from the presence of Oct 2.4 and 2.5 in neuronal cells and their absence in other cell types. The significance of this effect is discussed in terms of the role of Oct-2 in the regulation of viral and cellular gene expression in neuronal cells.

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Regulated splicing of the Oct-2 transcription factor RNA in neuronal cells

Neuroscience Letters ◽

10.1016/0304-3940(94)11102-o ◽

1995 ◽

Vol 183 (1-2) ◽

pp. 8-12 ◽

Cited By ~ 8

Author(s):

Yu-Zhen Liu ◽

Karen A. Lillycrop ◽

David S. Latchman

Keyword(s):

Transcription Factor ◽

Neuronal Cells

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Quantitative Proteome and Transcriptome Dynamics Analysis Reveals Iron Deficiency Response Networks and Signature in Neuronal Cells

Molecules ◽

10.3390/molecules27020484 ◽

2022 ◽

Vol 27 (2) ◽

pp. 484

Author(s):

Luke Erber ◽

Shirelle Liu ◽

Yao Gong ◽

Phu Tran ◽

Yue Chen

Keyword(s):

Transcription Factor ◽

Iron Deficiency ◽

Neuronal Development ◽

Cultured Cells ◽

Neurological Diseases ◽

Acute Hypoxia ◽

Cell Cycle Control ◽

Neuronal Cells ◽

Adaptive Responses ◽

Study Results

Iron and oxygen deficiencies are common features in pathophysiological conditions, such as ischemia, neurological diseases, and cancer. Cellular adaptive responses to such deficiencies include repression of mitochondrial respiration, promotion of angiogenesis, and cell cycle control. We applied a systematic proteomics analysis to determine the global proteomic changes caused by acute hypoxia and chronic and acute iron deficiency (ID) in hippocampal neuronal cells. Our analysis identified over 8600 proteins, revealing similar and differential effects of each treatment on activation and inhibition of pathways regulating neuronal development. In addition, comparative analysis of ID-induced proteomics changes in cultured cells and transcriptomic changes in the rat hippocampus identified common altered pathways, indicating specific neuronal effects. Transcription factor enrichment and correlation analysis identified key transcription factors that were activated in both cultured cells and tissue by iron deficiency, including those implicated in iron regulation, such as HIF1, NFY, and NRF1. We further identified MEF2 as a novel transcription factor whose activity was induced by ID in both HT22 proteome and rat hippocampal transcriptome, thus linking iron deficiency to MEF2-dependent cellular signaling pathways in neuronal development. Taken together, our study results identified diverse signaling networks that were differentially regulated by hypoxia and ID in neuronal cells.

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