MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation

EMBO J. 2004 Aug 18;23(16):3325-35. doi: 10.1038/sj.emboj.7600335. Epub 2004 Jul 29.

Abstract

The regulation of cell mass (cell growth) is often tightly coupled to the cell division cycle (cell proliferation). Ribosome biogenesis and the control of rDNA transcription through RNA polymerase I are known to be critical determinants of cell growth. Here we show that granulocytic cells deficient in the c-MYC antagonist MAD1 display increased cell volume, rDNA transcription and protein synthesis. MAD1 repressed and c-MYC activated rDNA transcription in nuclear run-on assays. Repression of rDNA transcription by MAD1 was associated with its ability to interact directly with the promoter of upstream binding factor (UBF), an rDNA regulatory factor. Conversely, c-MYC activated transcription from the UBF promoter. Using siRNA, UBF was shown to be required for c-MYC-induced rDNA transcription. These data demonstrate that MAD1 and c-MYC reciprocally regulate rDNA transcription, providing a mechanism for coordination of ribosome biogenesis and cell growth under conditions of sustained growth inhibition such as granulocyte differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins
  • Cell Differentiation*
  • Cells, Cultured
  • DNA, Ribosomal / biosynthesis
  • DNA, Ribosomal / genetics*
  • Gene Expression Regulation
  • Granulocytes / cytology
  • Granulocytes / metabolism*
  • Humans
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphoproteins / deficiency
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Pol1 Transcription Initiation Complex Proteins / metabolism*
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Transcription, Genetic / genetics*

Substances

  • Cell Cycle Proteins
  • DNA, Ribosomal
  • MAD1L1 protein, human
  • Mad1l1 protein, mouse
  • Nuclear Proteins
  • Phosphoproteins
  • Pol1 Transcription Initiation Complex Proteins
  • Proto-Oncogene Proteins c-myc
  • Repressor Proteins
  • transcription factor UBF