Open AccessA Functional Screen for Regulators of CKDN2A Reveals MEOX2 as a Transcriptional Activator of INK4a
Author(s) -
Jeffrey T. Irelan,
Ana Gutierrez del Arroyo,
Abel Gutierrez,
Gordon Peters,
Kim Quon,
Loren Miraglia,
Sumit K. Chanda
Publication year - 2009
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0005067
Subject(s) - biology , chromatin immunoprecipitation , homeobox , transcription factor , transcriptional regulation , activator (genetics) , senescence , gene , chromatin , promoter , regulation of gene expression , transcription (linguistics) , genetics , complementary dna , microbiology and biotechnology , junb , gene expression , philosophy , linguistics
The CDKN2A locus encodes two important tumor suppressors, INK4a and ARF, which respond to oncogenic stresses by inducing cellular senescence. We conducted a genome-scale cDNA overexpression screen using a reporter containing INK4a regulatory sequences to identify novel transcriptional activators of this locus. This screen revealed 285 cDNAs that putatively regulate the transcriptional activation of INK4a. Of these, 56 are annotated as transcription factors, including two previously reported activators of the locus, ETS2 and JUNB. Fourteen genes were further validated for activity and specificity, including several homeodomain proteins. We found that the transcription of one of these, the homeodomain protein MEOX2 (GAX) is enhanced in primary cells during the induction of senescence, and forced expression of this protein results in the induction of premature senescence. We further demonstrate that MEOX2-induced senescence is dependent upon INK4a activity, and chromatin immunoprecipitation studies indicate that MEOX2 directly binds the INK4a promoter. These results support a role for this homeodomain protein as a direct regulator of INK4a transcription and senescence in human cells.