Combinatorial action of transcription factors orchestrates cell cycle‐dependent expression of the ribosomal protein genes and ribosome biogenesis

Abstract

Nucleolar assembly begins at the early G1 phase of the cell cycle and is a hub of ribosomal DNA transcription and rRNA biosynthesis. The newlyformed rRNAs together with ribosomal proteins (RPs) constitute the building block of the ribosomal machinery. Although RPs play a major role in protein biosynthesis, their own regulation and expression is rather poorly understood. In the present study, we investigated the regulation of RP genes RPS27a, RPS24, RPS6, RPL9 and RPL4 in synchronized mammalian cell culture. Quantitative RT-PCR analysis indicated their expression during the mid to late G1 phase, whereas the rRNA genes were expressed during the early G1 phase of the cell cycle. The promoter reporter analysis of the RPS27a gene revealed that it could be synergistically stimulated by the transcription factors specificity protein 1 (Sp1) and cAMP response element-binding protein (CREB). However, E2F transcription factor 1 (E2F1) appeared to negatively regulate gene expression. Chromatin immunoprecipitation studies confirmed the promoter occupancy of Sp1, CREB and E2F1. Although Sp1 and CREB binding enhanced the promoter occupancy of histone acetyltransferases PCAF, p300 and CREB binding protein, E2F1 facilitated the recruitment of histone deacetylases. Both acetylation (histone H4 pan-acetyl, histone H3 acetyl Lys 14) and methylation (histone H3 trimethyl Lys 9) marks were observed in the RPS27a promoter region, suggesting their important regulatory role in gene expression. Because the promoter regions of most RP genes are well conserved, we propose that their orchestrated regulation and synthesis during the cell cycle facilitates ribosome biogenesis.

The Predicted Key Molecules, Functions, and Pathways That Bridge Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD)

“…RPS27A is synthesized as a C-terminal extension of ubiquitin, while ubiquitin is involved in DNA repair, cell-cycle regulation, and protein degradation via the proteasome. The expression of RPS27A is specifically induced in the middle and late G1 phase of the cell cycle, mainly to ensure that the biological process of the cell cycle proceeds smoothly (45). We recognized RPS27A showed decreased expression level comparing with normal samples, indicating that reduced RPS27A expression might be involved in the development of MCI through conducting to arrest of cell cycle.…”

“…that cell cycle-related proteins exhibit abnormal expression in hippocampal neurons of patients with MCI (44,45). RPS27A is synthesized as a C-terminal extension of ubiquitin, while ubiquitin is involved in DNA repair, cell-cycle regulation, and protein degradation via the proteasome.…”

Effect of mTORC1/mTORC2 inhibition on T cell function: potential role in graft‐versus‐host disease control

“…On the other hand, not only phosphorylation but also expression of both RPS6 and 4E‐BP1 was reduced upon mTOR inhibition. It has been shown that the synthesis of ribosomal proteins, such as RPS6, is tightly linked to cell cycle progression and remains low during the G 0 phase (Nosrati et al , ), as observed in resting T cells. Thus, it is probable that the antiproliferative effect induced by mTOR inhibitors impairs the expression of RPS6.…”

REPA: Applying Pathway Analysis to Genome-Wide Transcription Factor Binding Data

“…A large number of TFs have been implicated in ribosome biogenesis; for instance, roughly 80 factors have been associated in the maturation of the 60S subunit [38]. REPA predicted the following 38 TFs to be associated with the KEGG ribosome pathway (supporting literature is referred to after the corresponding TF): ATF1, ATF2, ATF3, BCL3, BCLAF1, CBX3, CEBPB, CJUN, CREB1 [39], ELF1 [40], ETS1, GABP [41], GR [42], HEY1, IRF3, MTA3, MYBL2, NFATC1, NFIC, NRSF, PML [43], POL2 [37], POU2F2, RFX5, RUNX3, SIN3AK20, SIX5, SP1 [41], SP4, STAT5A, TAF1 [44], TAF7, TBLR1, TCF12, WHIP, YY1 [41], ZNF143, and ZNF263. Thus, we found literature support for 9 (or 24%) of these TFs.…”