Liver tumor formation by a mutant retinoblastoma protein in the transgenic mice is caused by an upregulation of c-Myc target genes

Bo Wang, Keisuke Hikosaka, Nishat Sultana, Mohammad Tofael Kabir Sharkar, Hidenao Noritake, Wataru Kimura, Yi Xin Wu, Yoshimasa Kobayashi, Tadayoshi Uezato, Naoyuki Miura

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

The retinoblastoma (Rb) tumor suppressor encodes a nuclear phosphoprotein that regulates cellular proliferation, apoptosis and differentiation. In order to adapt itself to these biological functions, Rb is subjected to modification cycle, phosphorylation and dephosphorylation. To directly determine the effect of phosphorylation-resistant Rb on liver development and function, we generated transgenic mice expressing phosphorylation-resistant human mutant Rb (mt-Rb) under the control of the rat hepatocyte nuclear factor-1 gene promoter/enhancer. Expression of mt-Rb in the liver resulted in macroscopic neoplastic nodules (adenomas) with ~50% incidence within 15. months old. Interestingly, quantitative reverse transcriptase-PCR analysis showed that c-Myc was up-regulated in the liver of mt-Rb transgenic mice irrespective of having tumor tissues or no tumor. In tumor tissues, several c-Myc target genes, Foxm1, c-Jun, c-Fos, Bmi1 and Skp2, were also up-regulated dramatically. We determined whether mt-Rb activated the Myc promoter in the HTP9 cells and demonstrated that mt-Rb acted as an inhibitor of wild-type Rb-induced repression on the Myc promoter. Our results suggest that continued upregulation of c-Myc target genes promotes the liver tumor formation after about 1. year of age.

Original languageEnglish
Pages (from-to)601-606
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume417
Issue number1
DOIs
StatePublished - 6 Jan 2012
Externally publishedYes

Keywords

  • AP-1
  • Bmi1
  • Foxm1
  • Liver tumor
  • Myc
  • Skp2

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