title: HDMX-L is expressed from a functional p53-responsive promoter in the first intron of the HDMX gene and participates in an autoregulatory feedback loop to control p53 activity.
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 up-regulated 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. 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.
authors.affiliation: Southampton Cancer Research UK Centre, University of Southampton School of Medicine, Southampton General Hospital, Southampton SO16 6YD, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Phillips
authors.forename: Amina
authors.initials: A
authors.lastname: Teunisse
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lam
authors.forename: Kirsten
authors.initials: K
authors.lastname: Lodder
authors.forename: Matthew
authors.initials: M
authors.lastname: Darley
authors.forename: Muhammad
authors.initials: M
authors.lastname: Emaduddin
authors.forename: Anja
authors.initials: A
authors.lastname: Wolf
authors.forename: Julia
authors.initials: J
authors.lastname: Richter
authors.forename: Job
authors.initials: J
authors.lastname: de Lange
authors.forename: Matty
authors.initials: M
authors.lastname: Verlaan-de Vries
authors.forename: Kristiaan
authors.initials: K
authors.lastname: Lenos
authors.forename: Anja
authors.initials: A
authors.lastname: Böhnke
authors.forename: Frank
authors.initials: F
authors.lastname: Bartel
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Blaydes
authors.forename: Aart G
authors.initials: AG
authors.lastname: Jochemsen
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004318:Doxycycline / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D019143:Evolution, Molecular; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007438:Introns / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; D007093:Imidazoles; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D005047:Etoposide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D004318:Doxycycline