MYCN acts as a direct co-regulator of p53 in MYCN amplified neuroblastoma

Oncotarget
Saurabh AgarwalJason M Shohet

Abstract

The MYC oncogenes and p53 have opposing yet interrelated roles in normal development and tumorigenesis. How MYCN expression alters the biology and clinical responsiveness of pediatric neuroblastoma remains poorly defined. Neuroblastoma is p53 wild type at diagnosis and repression of p53 signaling is required for tumorigenesis. Here, we tested the hypothesis that MYCN amplification alters p53 transcriptional activity in neuroblastoma. Interestingly, we found that MYCN directly binds to the tetrameric form of p53 at its C-terminal domain, and this interaction is independent of MYCN/MAX heterodimer formation. Chromatin analysis of MYCN and p53 targets reveals dramatic changes in binding, as well as co-localization of the MYCN-p53 complex at p53-REs and E-boxes of genes critical to DNA damage responses and cell cycle progression. RNA sequencing studies show that MYCN-p53 co-localization significantly modulated the expression of p53 target genes. Furthermore, MYCN-p53 interaction leads to regulation of alternative p53 targets not regulated in the presence of low MYCN levels. These novel targets include a number of genes involved in lipid metabolism, DNA repair, and apoptosis. Taken together, our findings demonstrate a novel oncogeni...Continue Reading

References

Aug 6, 2004·Proceedings of the National Academy of Sciences of the United States of America·Eva GrönroosJohan Ericsson
Jan 13, 2005·Proceedings of the National Academy of Sciences of the United States of America·Andrew SlackJason M Shohet
Sep 21, 2006·Molecular Cancer Therapeutics·Eveline BarbieriJason M Shohet
Sep 7, 2007·Nature·Jing HuangShelley L Berger
Dec 3, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Susan L CohnUNKNOWN INRG Task Force
Jan 10, 2009·Nature Protocols·Da Wei HuangRichard A Lempicki
Jul 21, 2009·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Alberto GaraventaRiccardo Haupt
Nov 3, 2009·The Lancet Oncology·Joëlle VermeulenJo Vandesompele
Jun 3, 2010·Cold Spring Harbor Perspectives in Biology·Andreas C Joerger, Alan R Fersht
Aug 4, 2010·Cold Spring Harbor Perspectives in Biology·Rachel Beckerman, Carol Prives
Mar 12, 2011·PloS One·Leonie SmeenkMarion Lohrum
Apr 5, 2011·Nucleic Acids Research·Max KoeppelMarion Lohrum
Jul 20, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Wendy B LondonKatherine K Matthay
Dec 1, 2011·Cell Cycle·Krassimira BotchevaCarl W Anderson
Dec 20, 2011·Journal of Molecular Biology·Hyunjung KimWoojin An
Apr 18, 2012·Genes & Development·Phi M DoLuis A Martinez
May 19, 2012·International Journal of Biological Sciences·Bo Gu, Wei-Guo Zhu
Sep 6, 2013·Proceedings of the National Academy of Sciences of the United States of America·Giorgio GagliaGalit Lahav
Oct 15, 2013·Cell·Denes HniszRichard A Young
Jan 5, 2014·Cold Spring Harbor Perspectives in Medicine·Maralice Conacci-SorrellRobert N Eisenman
Oct 26, 2014·Molecular Systems Biology·Giorgio Gaglia, Galit Lahav
Nov 12, 2014·Annual Review of Medicine·Chrystal U Louis, Jason M Shohet
Jun 30, 2015·Nature Genetics·Alexander SchrammJohannes H Schulte
Jun 30, 2015·Nature Genetics·Thomas F EleveldJohn M Maris
Jul 2, 2015·International Journal of Cancer. Journal International Du Cancer·Kazushi InoueDonna P Frazier
Sep 19, 2015·Cancer Discovery·Zachary E StineChi V Dang
Sep 22, 2015·Cell Metabolism·Brian J AltmanChi V Dang
Oct 23, 2015·Cell Death & Disease·E S Kim, J M Shohet
Mar 20, 2016·Oncotarget·Saurabh AgarwalJason M Shohet
Dec 8, 2016·Cancer Research·MoonSun JungMichelle J Henderson
Feb 10, 2017·Journal of Biomedical Science·Maria Rosaria EspositoGian Paolo Tonini
Mar 3, 2017·Cell Death & Disease·Theresa M TholeHedwig E Deubzer
May 2, 2017·Oncogene·R R OlsenK W Freeman

❮ Previous
Next ❯

Citations

Jul 29, 2018·Journal of Experimental & Clinical Cancer Research : CR·Go J Yoshida
May 28, 2019·Journal of Experimental & Clinical Cancer Research : CR·Jinguan LinQianjin Liao
Dec 31, 2019·Oxidative Medicine and Cellular Longevity·Amnah M AlshangitiGerard W O'Keeffe
Jun 25, 2020·Japanese Journal of Clinical Oncology·Yusuke SuenagaAkira Nakagawara
Feb 12, 2020·Cancer Research·Natalie AnderssonDavid Gisselsson
Aug 1, 2019·International Journal of Molecular Sciences·Kiyohiro AndoMakoto Makishima
Feb 2, 2021·Cancer Treatment Reviews·Michael J DuffyJohn Crown
Jun 6, 2021·Molecular Cancer Therapeutics·Krista M DaltonAnthony C Faber

❮ Previous
Next ❯

Datasets Mentioned

BETA
GSE83328
GSE83317

Methods Mentioned

BETA
acetylation
proximity ligation
co-immunoprecipitation
transfection
pulldown
co-IP
pull-down
pull down
RNA-Seq
cross-ChIP

Software Mentioned

GSEA
BEDTOOLS
Gene Set Enrichment Analysis ( GSEA )
TopHat2
MeV
scipy
DAVID
Gene Set Enrichment Analysis ( GSEA
numpy
Integrative Genomics Viewer Browser

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.

Cancer Epigenetics Chromatin Complexes (Keystone)

Epigenetic changes are present and dysregulated in many cancers, including DNA methylation, non-coding RNA segments and post-translational protein modifications. The epigenetic changes may or may not provide advantages for the cancer cells. This feed focuses on chromatin complexes and their role in cancer epigenetics.

Cancer Epigenetics and Chromatin (Keystone)

Epigenetic changes are present and dysregulated in many cancers, including DNA methylation, non-coding RNA segments and post-translational protein modifications. The epigenetic changes may or may not provide advantages for the cancer cells. This feed focuses on chromatin and its role in cancer epigenetics please follow this feed to learn more.