Skip to main content
Article thumbnail
Location of Repository

HDMX-L is expressed from a functional P53-responsive promoter in the first intron of the HDMX gene, and participates in an auto-regulatory feedback loop to control P53 activity.

By Anna Phillips, Amina Teunisse, Suzanne Lam, Kirsten Lodder, Matthew Darley, Muhammad Emaduddin, Anja Wolf, Julia Richter, Job de Lange, Matty Verlaan-de Vries, Kristiaan Lenos, Anja Boehnke, Frank Bartel, Jeremy P. Blaydes and Aart G. Jochemsen

Abstract

The p53 regulatory network is critically involved in preventing the initiation of cancer. In unstressed cells p53 is maintained at low levels and is largely inactive, mainly through the action of its two essential negative regulators, HDM2 and HDMX. p53 abundance and activity are upregulated in response to various stresses including DNA damage and oncogene activation. Active p53 initiates transcriptional and transcription-independent programs that result in cell cycle arrest, cellular senescence or apoptosis. p53 also activates transcription of HDM2, which initially leads to the degradation of HDMX, creating a positive feedback loop to obtain maximal activation of p53. Subsequently, when stress-induced post-translational modifications start to decline, HDM2 becomes effective in targeting p53 for degradation, thus attenuating the p53 response. <br/><br/>To date, no clear function for HDMX in this critical attenuation phase has been demonstrated experimentally. Like HDM2, the HDMX gene contains a promoter (P2) in its first intron that is potentially inducible by p53. We show that p53 activation in response to a plethora of p53-activating agents induces the transcription of a novel HDMX mRNA transcript from the HDMX-P2 promoter. This mRNA is more efficiently translated than that expressed from the constitutive HDMX-P1 promoter, and it encodes a long form of HDMX protein, HDMX-L. Importantly, we demonstrate that HDMX-L cooperates with HDM2 to promote the ubiquitination of p53, and that p53-induced HDMX transcription from the P2 promoter can play a key role in the attenuation phase of the p53-response, to effectively diminish p53 abundance as cells recover from stress

Topics: QD, QH426, QH301
Year: 2010
OAI identifier: oai:eprints.soton.ac.uk:161383
Provided by: e-Prints Soton

Suggested articles


To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.