Project B5

Dysregulation of p53 by MDM Proteins in Human Hepatocarcinogenesis

Principal Investigators: Dr. T. Longerich, Prof. Dr. P. Schirmacher, Dr. B. Radlwimmer


Short Summary

The inactivation of p53 is one of the key events in carcinogenesis, but in contrast to other carcinomas Western HCCs display a surprisingly low frequency of p53 mutations. We have shown that an upregulation of MDM4 and MDM2 contributes to p53 inactivation in HCCs. This project aims at determining the relevance and underlying mechanisms of MDM2/4 dysregulation in human HCCs by analyzing their expression regulation in detail (promoter mutation, and methylation analyses, microRNA-dependent regulation etc.) The in vivo hepatocarcinogenic potential of MDM2 and MDM4 will be addressed by adequate mouse models.


List of relevant publications

  1. Breinig M, Caldas-Lopes E, Goeppert B, Malz M, Bergmann F, Rieker R, Schirmacher P, Mayer MP, Chiosis G, Kern MA (2009) Targeting the heat shock protein Hsp90 with non-quinone inhibitors: A novel chemotherapeutic approach in human hepatocellular carcinoma. Hepatology (in press).
  2. Nussbaum T, Samarin J, Ehemann V, Bissinger M, Ryschich E, Khamidjanov A, Yu X, Gretz N, Schirmacher P, Breuhahn K (2008) Autocrine insulin-like growth factor-II stimulation of tumor cell migration is a progression step in human hepatocarcinogenesis. Hepatology 48:146-56.
  3. Varnholt H, Drebber U, Schulze F, Wedemeyer I, Schirmacher P, Dienes HP, Odenthal M (2008) MicroRNA gene expression profile of hepatitis C virus-associated hepatocellular carcinoma. Hepatology 47:1223-32.
  4. Zender L, Xue W, Zuber J, Semighini CP, Krasnitz A, Ma B, Zender P, Kubicka S, Luk JM, Schirmacher P, McCombie WR, Wigler M, Hicks J, Hannon GJ, Powers S, Lowe SW (2008) An oncogenomics-based in vivo RNAi screen identifies tumor suppressors in liver cancer. Cell 135:852-64.
  5. Schlaeger* C, Longerich* T, Schiller C, Bewerunge P, Mehrabi A, Toedt G, Kleeff J, Ehemann V, Eils R, Lichter P, Schirmacher P, Radlwimmer B (2008) Etiology-dependent molecular mechanisms in human hepatocarcinogenesis. Hepatology 47:511-20; *equal contribution.
  6. Lechel A, Holstege H, Begus Y, Schienke A, Kamino K, Lehmann U, Kubicka S, Schirmacher P, Jonkers J, Rudolph KL (2007) Telomerase deletion limits progression of p53-mutant hepatocellular carcinoma with short telomeres in chronic liver disease. Gastroenterology 132:1465-75.
  7. Schaetzlein S, Kodandaramireddy NR, Ju Z, Lechel A, Stepczynska A, Lilli DR, Clark AB, Rudolph C, Kuhnel F, Wei K, Schlegelberger B, Schirmacher P, Kunkel TA, Greenberg RA, Edelmann W, Rudolph KL (2007) Exonuclease-1 deletion impairs DNA damage signaling and prolongs lifespan of telomere-dysfunctional mice. Cell 130:863-77.
  8. Breinig M, Rieker R, Eiteneuer E., Wertenbruch T, Haugg AM, Helmke BM, Schirmacher P, Kern MA (2007) Differential expression of E-prostanoid receptors in human hepatocellular carcinoma. Int J Cancer 122:547-57.
  9. Singer S, Ehemann V, Brauckhoff A, Keith M, Vreden S, Schirmacher P, Breuhahn K (2007) Protumorigenic overexpression of stathmin/Op18 by gain-of-function mutation in p53 in human hepatocarcinogenesis. Hepatology 46:759-68.
  10. Choudhury AR, Ju Z, Djojosubroto MW, Schienke A, Lechel A, Schaetzlein S, Jiang H, Stepczynska A, Wang C, Buer J, Lee HW, von Zglinicki T, Ganser A, Schirmacher P, Nakauchi H, Rudolph KL (2007) Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat Genet 39:99-105.
  11. Breuhahn K, Longerich T, Schirmacher P (2006) Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene 25:3787-800.
  12. Moinzadeh P, Breuhahn K, Stutzer H, Schirmacher P (2005) Chromosome alterations in human hepatocellular carcinomas correlate with aetiology and histological grade - results of an explorative CGH meta-analysis. Br J Cancer 92:935-41.
  13. Breuhahn K, Vreden S, Haddad R, Beckebaum S, Stippel D, Flemming P, Nussbaum T, Caselmann WH, Haab BB, Schirmacher P (2004) Molecular Profiling of Human Hepatocellular Carcinoma Defines Mutually Exclusive Interferon Regulation and Insulin-Like Growth Factor II Overexpression. Cancer Res 64:6058-64.
  14. Longerich T, Breuhahn K, Odenthal M, Petmecky K, Schirmacher P (2004) Factors of transforming growth factor beta signalling are co-regulated in human hepatocellular carcinoma. Virchows Arch 445:589-96.
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