PKB-mediated PHF20 phosphorylation on Ser291 is required for p53 function in DNA damage

Abstract

Publisher rights This is the author's version of a work that was accepted for publication in Cellular Signalling. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Cellular Signalling, VOL25, ISSUE1, 01/2013General rights Copyright for the publications made accessible via the Queen's University Belfast Research Portal is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Running Head: Regulation of PHF20 by PKB Keywords : PHF20, Glioblastoma, PKB, p53, protein phosphorylation A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT2 Abstract PHD finger protein 20 (PHF20) is a transcription factor, which was originally identified in glioma patients. PHF20 appears to be a novel antigen in glioma, and has also termed gliomaexpressed antigen 2. PHF20 is thought to contribute to the development of cancers, including glioblastoma, lung cancer, colon cancer and ovarian cancer. However, little is known about the function of PHF20 in various cancers. Here we report that PHF20 contains two consensus sites for protein kinase B (PKB) phosphorylation (RxRxxS/T). PKB can directly phosphorylate PHF20 on Ser291 in vitro and in vivo. It has been shown that PKB participates in the tumor suppressor p53 regulated gene expression program and has a direct effect on p21 regulation after DNA damage. UV induced DNA damage result in accumulation of p53 and PKB activation. Interestingly, PKB-mediated PHF20 phosphorylation led to an inhibition of p53 induction following UV treatment, leading to the reduction of p21 transcriptional activity.Using anti PHF20 and anti pPKB (S473) antibodies, these events were mapped in various human cancer tissues. Taken together, these data suggest that PHF20 is a novel substrate for PKB and its phosphorylation by PKB plays an important role in tumorigenesis via regulating of p53 mediated signaling.

PHF20 regulates NF-κB signalling by disrupting recruitment of PP2A to p65

“…Recent reports indicated that PHF20 was phosphorylated at Ser291 and Ser265 by Akt/PKB 29,30 . Here, we further assessed whether the phosphorylation status of PHF20 is functionally involved in its effect on p65 phosphorylation.…”

PHF20 positively regulates osteoblast differentiation via increasing the expression and activation of Runx2 with enrichment of H3K4me3

“…The activity of Runx2 is precisely regulated by other interacting proteins 25 . PHF20 can also interact with other proteins to control cellular activity along with methylation and acetylation processes of proteins 19 , 26 . For example, PHF20 can function as an effector of p53 methylation to stabilize and activate the protein 19 .…”

“…Reporter constructs containing mouse Osteocalcin gene 2 promoters-Luciferase (Og2-Luc) construct was kindly provided by Dr. Renny T Franceschi (University of Michigan School of Dentistry, Ann Arbor, MI, USA). Full length PHF20 (Flag-PHF20) and adenovirus PHF20 (Ad-PHF20) were previously described 26 .…”

Jmjd3 Inhibits Reprogramming by Upregulating Expression of INK4a/Arf and Targeting PHF20 for Ubiquitination

“…PHF20 has since been identified as a histone code reader that specifically recognizes the dimethylation of H3K4, H3K9, H4K20, and H4K79 (Adams-Cioaba et al, 2012; Kim et al, 2006). Recent studies show that it also regulates p53 protein at both the transcriptional and posttranscriptional levels in response to DNA damage (Li et al, 2012b; Park et al, 2012). Mice with PHF20 ablation die shortly after birth (Badeaux et al, 2012).…”