Use of Forward Genetics to Discover Novel Regulators of NF- B

Lü, Tao; Stark, George R.

doi:10.1101/cshperspect.a001966

Cited by 9 publications

(6 citation statements)

References 45 publications

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“…Alternatively,some methyl transferases may be pre-associated with some promoters before NF-κB arrives. (This figure is adapted from references 19, 20)…”

Section: Fig1mentioning

confidence: 99%

NF-κB: Regulation by Methylation

Lü

Stark

2015

Cancer Research

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In normal cells exposed to stress, the central transcription factor nuclear factor κB (NF-κB) is activated only transiently, to modulate the activation of downstream immune responses. However, in most cancers, NF-κB is abnormally activated constitutively, contributing thus to oncogenesis and tumor progression. Therefore, down regulating NF-κB activity is an important goal of cancer treatment. In order to control NF-κB activity therapeutically, it is helpful to understand the molecular mechanisms that normally govern its activation, and how dysregulated NF-κB activity may aid the development of disease. Recent evidence from our labs (1-4) and others (5-7) indicates that, in addition to various post-translational modifications of NF-κB that have been observed previously, including phosphorylation, ubiquitination, and acetylation, NF-κB can be methylated reversibly on lysine or arginine residues by histone modifying enzymes, including lysine and arginine methyl transferases and demethylases. Furthermore, these methylations are required to activate many downstream genes. Interestingly, amplifications and mutations of several such enzymes have been linked to cancer. We propose that some of these mutations may alter the methylation not only of histones but also of NF-κB, making them attractive therapeutic targets.

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“…Alternatively,some methyl transferases may be pre-associated with some promoters before NF-κB arrives. (This figure is adapted from references 19, 20)…”

Section: Fig1mentioning

confidence: 99%

NF-κB: Regulation by Methylation

Lü

Stark

2015

Cancer Research

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“…The nuclear factor-kappa B (NF-jB) signaling pathway is pivotal for a wide array of cellular processes [1][2][3][4][5]. Albeit the signaling cascade that leads to NF-jB activation has been extensively studied [6][7][8][9][10][11], it remains elusive how NF-jB specifically activates its target genes [12][13][14][15]. Ribosomal protein S3 (RPS3) was identified as an essential component in NF-jB complexes where RPS3 can interact with the NF-jB p65 subunit in the cytoplasm and the nucleus [16].…”

Section: Introductionmentioning

confidence: 99%

Caspase‐3 cleaved p65 fragment dampens NF‐κB‐mediated anti‐apoptotic transcription by interfering with the p65/RPS3 interaction

Wier

Hodgson

et al. 2015

FEBS Letters

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Caspase-3-mediated p65 cleavage is believed to suppress nuclear factor-kappa B (NF-κB)-mediated anti-apoptotic transactivation in cells undergoing apoptosis. However, only a small percentage of p65 is cleaved during apoptosis, not in proportion to the dramatic reduction in NF-κB transactivation. Here we show that the p651-97 fragment generated by Caspase-3 cleavage interferes with ribosomal protein S3 (RPS3), an NF-κB “specifier” subunit, and selectively retards the nuclear translocation of RPS3, thus dampening the RPS3/NF-κB-dependent anti-apoptotic gene expression. Our findings reveal a novel cell fate determination mechanism to ensure cells undergo programed cell death through interfering with the RPS3/NF-κB-conferred anti-apoptotic transcription by the fragment from partial p65 cleavage by activated Caspase-3.

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“…The VBIM system has been successfully utilized in studying NF-KB signaling pathway [20] . This insertional mutagenesis system was constructed based on lentiviral vector.…”

Section: Resultsmentioning

confidence: 99%

Forward Genetic Screening for Regulators Involved in Cholesterol Synthesis Using Validation-Based Insertional Mutagenesis

et al. 2014

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Somatic cell genetics is a powerful approach for unraveling the regulatory mechanism of cholesterol metabolism. However, it is difficult to identify the mutant gene(s) due to cells are usually mutagenized chemically or physically. To identify important genes controlling cholesterol biosynthesis, an unbiased forward genetics approach named validation-based insertional mutagenesis (VBIM) system was used to isolate and characterize the 25-hydroxycholesterol (25-HC)-resistant and SR-12813-resisitant mutants. Here we report that five mutant cell lines were isolated. Among which, four sterol-resistant mutants either contain a truncated NH2-terminal domain of sterol regulatory element-binding protein (SREBP)-2 terminating at amino acids (aa) 400, or harbor an overexpressed SREBP cleavage-activating protein (SCAP). Besides, one SR-12813 resistant mutant was identified to contain a truncated COOH-terminal catalytic domain of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase). This study demonstrates that the VBIM system can be a powerful tool to screen novel regulatory genes in cholesterol biosynthesis.

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Use of Forward Genetics to Discover Novel Regulators of NF- B

Cited by 9 publications

References 45 publications

NF-κB: Regulation by Methylation

NF-κB: Regulation by Methylation

Caspase‐3 cleaved p65 fragment dampens NF‐κB‐mediated anti‐apoptotic transcription by interfering with the p65/RPS3 interaction

Forward Genetic Screening for Regulators Involved in Cholesterol Synthesis Using Validation-Based Insertional Mutagenesis

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