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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
ING1a expression increases during replicative senescence and induces a senescent phenotype
Aging Cell, Volume 7, No. 6, Year 2008
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Description
The ING family of tumor suppressor proteins affects cell growth, apoptosis and response to DNA damage by modulating chromatin structure through association with different HAT and HDAC complexes. The major splicing isoforms of the ING1 locus are ING1a and INGlb. While INGlb plays a role in inducing apoptosis, the function of ING1a is currently unknown. Here we show that alternative splicing of the ING1 message alters the INGla:INGlb ratio by ∼30-fold in senescent compared to low passage primary fibroblasts. INGla antagonizes INGlb function in apoptosis, induces the formation of structures resembling senescence-associated heterochromatic foci containing heterochromatin protein.1.gamma, the accumulation of senescence-associated β-galactosidase activity and promotes senescent cell morphology and cell cycle arrest. Phenotypic effects may result from differential effects on gene expression since ING1a increases levels of both retinoblastoma and the p16 cyclin-dependent kinase inhibitor and ING1a and ING1b have opposite effects on the expression of proliferating nuclear cell antigen (PCNA), which is required for cell growth. Gene expression appears to be altered by targeting of HDAC complexes to gene promoters since INGla associates with several-fold higher levels of HDAC1 in senescent, compared to replication-competent cells and ING1 is found on the PCNA promoter by chromatin immunoprecipitation analysis. These data demonstrate a novel role for the ING1 proteins in differentially regulating senescence-associated chromatin remodeling vs. apoptosis and support the idea that altered ratios of the ING1 splicing isoforms may contribute to establishing the senescent phenotype through HDAC and HAT complex-mediated effects on chromatin structure. © 2008 The Authors Journal compilation © 2008 Blackwell Publishing Ltd/The Anatomical Society of Great Britain and Ireland.
Authors & Co-Authors
Soliman, M. A.
Canada, Calgary
Cumming School of Medicine
Egypt, Cairo
Faculty of Pharmacy
Berardi, Philip
Canada, Calgary
Cumming School of Medicine
Pastyryeva, Svitlana
Canada, Calgary
Cumming School of Medicine
Bonnefin, Paul
Canada, Calgary
Cumming School of Medicine
Australia, Parramatta
Children's Medical Research Institute
Feng, Xiaolan
Canada, Calgary
Cumming School of Medicine
Colina, Ana
Canada, Calgary
Cumming School of Medicine
Young, Dallan
Canada, Calgary
Cumming School of Medicine
Canada, Calgary
University of Calgary
Riabowol, Karl
Canada, Calgary
Cumming School of Medicine
Canada, Calgary
University of Calgary
Statistics
Citations: 50
Authors: 8
Affiliations: 4
Identifiers
Doi:
10.1111/j.1474-9726.2008.00427.x
ISSN:
14749718
e-ISSN:
14749726
Research Areas
Cancer
Genetics And Genomics