hCAS/CSE1L Associates with Chromatin and Regulates Expression of Select p53 Target Genes

The p53 tumor suppressor protein regulates many genes that can determine different cellular outcomes such as growth arrest or cell death. Promoter-selective transactivation by p53, although critical for the different cellular outcomes, is not well understood. We report here that the human cellular a...

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Bibliographic Details
Published in:Cell 2007-08, Vol.130 (4), p.638-650
Main Authors: Tanaka, Tomoaki, Ohkubo, Shuichi, Tatsuno, Ichiro, Prives, Carol
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Breast Neoplasms - pathology
Cell Culture Techniques
Cell Line
Cell Line, Tumor
Cellular Apoptosis Susceptibility Protein - chemistry
Cellular Apoptosis Susceptibility Protein - isolation & purification
Cellular Apoptosis Susceptibility Protein - metabolism
Cellular Apoptosis Susceptibility Protein - physiology
Chromatin - metabolism
Chromatin Immunoprecipitation
Conserved Sequence
DNA
DNA Methylation
Female
Gene Expression Regulation
Gene Silencing
HCT116 Cells
Histones - metabolism
Humans
Kidney - cytology
Models, Biological
Molecular Sequence Data
Plasmids
Promoter Regions, Genetic
PROTEINS
RNA Interference
Sequence Homology, Amino Acid
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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Summary:The p53 tumor suppressor protein regulates many genes that can determine different cellular outcomes such as growth arrest or cell death. Promoter-selective transactivation by p53, although critical for the different cellular outcomes, is not well understood. We report here that the human cellular apoptosis susceptibility protein (hCAS/CSE1L) associates with a subset of p53 target promoters, including PIG3, in a p53-autonomous manner. Downregulation of hCAS/CSE1L decreases transcription from those p53 target promoters to which it preferentially binds and reduces apoptosis. In addition, hCAS/CSE1L silencing leads to increased methylation of histone H3 lysine 27 within the PIG3 gene. hCAS/CSE1L was previously shown to function as a nucleo-cytoplasmic transport factor, as does its closely related yeast homologue Cse1, which can also associate with chromatin and serve as a barrier protein that prevents spreading of heterochromatin. Thus, human CAS/CSE1L can bind select genes with significant functional consequences for p53-mediated transcription and determine cellular outcome.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2007.08.001