Loss of the candidate tumor suppressor BTG3 triggers acute cellular senescence via the ERK-JMJD3-p16(INK4a) signaling axis.
The B-cell translocation gene 3 (BTG3) is a member of the antiproliferative BTG gene family and a downstream target of p53. BTG3 also binds and inhibits E2F1. Although it connects functionally two major growth-regulatory pathways, the physiological role of BTG3 remains largely uncharacterized. Here, we present evidence that loss of BTG3 in normal cells induced cellular senescence, which was correlated with enhanced ERK-AP1 signaling and elevated expression of the histone H3K27me3 demethylase JMJD3/KDM6B, leading to acute induction of p16(INK4a). Importantly, we also found that BTG3 expression is specifically downregulated in prostate cancer, thus providing a physiological link with human cancers. Our data suggest that BTG3 may have a fail-safe role against tumorigenic progression.
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
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TY
Lin
Y-C
YC
Cheng
H-C
HC
Yang
W-C
WC
Lin
C-C
CC
Wang
P-L
PL
Lai
S-Y
SY
Shieh
D018797:Cell Cycle Proteins; D002460:Cell Line; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics
C424522:BTG3 protein, human; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011506:Proteins; D018808:Transcription Factor AP-1; D025521:Tumor Suppressor Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human; D048049:Extracellular Signal-Regulated MAP Kinases