MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation.
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.
Poortinga
Gretchen
G
Division of Research, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia.
Hannan
Katherine M
KM
Snelling
Hayley
H
Walkley
Carl R
CR
Jenkins
Anna
A
Sharkey
Kerith
K
Wall
Meaghan
M
Brandenburger
Yves
Y
Palatsides
Manuela
M
Pearson
Richard B
RB
McArthur
Grant A
GA
Hannan
Ross D
RD
D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002478:Cells, Cultured; D004275:DNA, Ribosomal / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D035463:Pol1 Transcription Initiation Complex Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*
D018797:Cell Cycle Proteins; D004275:DNA, Ribosomal; C501384:MAD1L1 protein, human; C501385:Mad1l1 protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; D035463:Pol1 Transcription Initiation Complex Proteins; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; C063844:transcription factor UBF