Nuclear LYRIC/AEG-1 interacts with PLZF and relieves PLZF-mediated repression.
LYRIC/AEG-1 and its altered expression have been linked to carcinogenesis in prostate, brain and melanoma as well as promoting chemoresistance and metastasis in breast cancer. LYRIC/AEG-1 function remains unclear, although LYRIC/AEG-1 is activated by oncogenic HA-RAS, through binding of c-myc to its promoter, which in turn regulates the key components of the PI3-kinase and nuclear factor-kappaB pathways. We have identified the transcriptional repressor PLZF as an interacting protein of LYRIC/AEG through a yeast two-hybrid screen. PLZF regulates the expression of genes involved in cell growth and apoptosis including c-myc. Coexpression of LYRIC/AEG-1 with PLZF leads to a reduction in PLZF-mediated repression by reducing PLZF binding to promoters. We have confirmed that nuclear LYRIC/AEG-1 and PLZF interact in mammalian cells via the N- and C termini of LYRIC/AEG-1 and a region C terminal to the RD2 domain of PLZF. Both proteins colocalize to nuclear bodies containing histone deacetylases, which are known to promote PLZF-mediated repression. Our data suggest one mechanism for cells with altered LYRIC/AEG-1 expression to evade apoptosis and increase cell growth during tumourigenesis through the regulation of PLZF repression.
Thirkettle
H J
HJ
Uro-Oncology Research Group, Cancer Research UK Cambridge Research Institute, Cambridge, UK.
Mills
I G
IG
Whitaker
H C
HC
Neal
D E
DE
D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D014158:Transcription, Genetic
D015815:Cell Adhesion Molecules; D051741:Kruppel-Like Transcription Factors; C483039:MTDH protein, human; D008565:Membrane Proteins; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C092037:ZBTB16 protein, human; D006655:Histone Deacetylases