Key Event Title
|Level of Biological Organization|
Key Event Components
|positive regulation of gene expression||cyclin-dependent kinase inhibitor||increased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Histone deacetylase inhibition leading to testicular toxicity||KeyEvent|
|Not Otherwise Specified||Moderate|
Key Event Description
p21 (CDKN1A; cyclin dependent kinase inhibitor 1A) binds to and inhibits the activity of cyclin-dependent kinase 2 or cyclin-dependent kinase 4 complexes, and regulates cell cycle progression in G1 phase. p21 is important for cell cycle regulation.
How It Is Measured or Detected
The p21 mRNA is measured with real-time RT-PCR technique using primers for p21 [Dayan, 2014]. Gene expression of p21 is measured with microarray technique using gene chips after cDNA preparation from total RNA extracted from the samples [Glaser, 2003, Hoshino, 2007]. Protein level of p21 is measured with Western blot analysis using anti-p21 antibody [Parajuli, 2014, Glaser, 2003].
Domain of Applicability
The p21 up-regulation by HDIs is well conserved between species from lower organism to mammals.
・FK228, a HDAC inhibitor, up-regulated p21 level in human esophageal cancer TE2 cells (Homo sapiens) [Hoshino, 2007].
・MAA, a HDAC inhibitor, induced p21 up-regulation in human prostate cancer cell lines (Homo sapiens) [Parajuli, 2014].
・MAA increases p21 expression in human bladder carcinoma cells, T24 (Homo sapiens) [Glaser, 2003].
・MAA up-regulated p21 expression in limbs of CD1 embryonic mice (Mus musculus) [Dayan, 2014].
Dayan C and Hales BF. (2014) Effects of ethylene glycol monomethyl ether and its metabolite, 2-methoxyacetic acid, on organogenesis stage mouse limbs in vitro. Birth Defects Res (Part B) 101:254-261
Glaser KB et al. (2003) Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. Mol Cancer Ther 2:151-163
Hoshino I et al. (2007) Gene expression profiling induced by histone deacetylase inhibitor, FK228, in human esophageal squamous cancer cells. Oncol Rep 18:585-592
Parajuli KR et al. (2014) Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis. Am J Clin Exp Urol 2:300-313