Myc is an oncoprotein that is involved in regulating both cell division and cell growth. Previous reports had indicated that Myc stimulated RNA polymerase III (Pol III), which synthesizes the 5S ribosomal RNA (rRNA), as well as RNA polymerase II (Pol II), which synthesizes the transcripts encoding the ribosomal proteins (see Oskarsson and Trumpp). Three groups report that Myc also stimulates RNA polymerase I (Pol I), which synthesizes the transcript for the pre-rRNA transcript for the 28S, 5.8S, and 18S rRNAs. Grewal et al. showed that in Drosophila, overexpression of dMyc increased rRNA transcript abundance, nucleolar size, and ribosome abundance, whereas hypomorphic alleles of dMyc resulted in decreases. These effects on ribosome biogenesis were specific in that overexpression of dp110 (the phosphoinositide 3-kinase catalytic subunit), which also causes increased cell size, did not increase ribosome biogenesis. Microarray analysis of larval transcripts indicated that dMyc stimulated the expression of a collection of genes involved in ribosome biogenesis, including the genes encoding Rpl135 (a Pol I subunit) and TIF-1A (a growth-regulated Pol I-associated factor). The importance of rRNA synthesis in mediating cell size increases in response to dMyc overexpression was reinforced by the inhibition of this effect of dMyc in Rpl135−/− cells. Grandori et al. and Arabi et al. investigated the effect of Myc on mammalian cells. Both groups reported that, in contrast to flies, Myc directly bound the rDNA promoter, which encodes the rRNA transcript that produces the 28S, 5.8S, and 18S rRNAs, through an E-box sequence. Grandori et al. also showed that c-Myc interacted with the TIF-1B (also known as SL1), which is a complex that is required for Pol I transcription. When c-Myc was abundant, more TIF-1B was bound to the rDNA promoter, and when c-Myc was deficient, less TIF-1B was bound. Both groups also reported localization of c-Myc to nucleoli under certain circumstances: inhibition of the proteasome (Arabi et al. and Grandori et al.) and following serum addition after a period of deprivation (Grandori et al.). These three reports provide evidence that Myc is a regulator of Pol I, directly in mammals and indirectly (through regulation of gene expression) in flies. Thus, Myc appears situated to be a master regulator of ribosome biogenesis through its effects on each of the three RNA polymerases.
T. Oskarsson, A. Trumpp, The Myc trilogy: lord of RNA polymerases. Nat. Cell Biol. 7, 215-217 (2005). [PubMed]
S. S. Grewal, L. Li, A. Orian, R. N. Eisenman, B. A. Edgar, Myc-dependent regulation of ribosomal RNA synthesis during Drosophila development. Nat. Cell Biol. 7, 295-302 (2005). [PubMed]
C. Grandori, N. Gomez-Roman, Z. A. Felton-Edkins, C. Ngouenet, D. A. Galloway, R. N. Eisenman, R. J. White, c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I. Nat. Cell Biol. 7, 311-318 (2005). [PubMed]
A. Arabi, S. Wu, K. Ridderstråle, H. Bierhoff, C. Shiue, K. Fatyol, S. Fahlén, P. Hydbring, O. Söderberg, I. Grummt, L.-G. Larsson, A. P. H. Wright, c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription. Nat. Cell Biol. 7, 303-310 (2005). [PubMed]