Ribosomal proteins are synthesized preferentially in cells commencing growth

Tushinski, Robert; Warner, Jonathan R.

doi:10.1002/jcp.1041120119

Cited by 69 publications

(32 citation statements)

References 29 publications

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“…Moreover, the Drosophila melanogaster, L13, is expressed at all stages of development, with the highest levels occurring during embryogenesis (48). These findings are consistent with it being a ribosomal protein, since the levels of transcription and translation are relatively high in growing cells (49,50). Considering the above findings together with our result showing that silencing L13 by siRNA inhibits cancer cell growth, it seems that the expression levels of L13 genes correlate with active cell division and cell growth.…”

Section: Discussionsupporting

confidence: 82%

Activation of the ribosomal protein L13 gene in human gastrointestinal cancer

Kobayashi

Sasaki²,

Oshima³

et al. 2006

Int J Mol Med

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Abstract. Although ribosomal proteins are major components of ribosomes, recent data have shown them to have extraribosomal functions apart from ribosome and protein biosynthesis. In our earlier study, we showed that ribosomal protein L13 mRNA was up-regulated in response to DNA damage in hamster cells. We report here that L13 expression is up-regulated in human gastrointestinal cancers. We also examined the biological role of L13 on human cancer cells. Knocking down L13 expression using small interfering RNA (siRNA) resulted in drastic attenuation of cancer cell growth with significant G1 and G2/M arrest of the cell cycle. Moreover, L13 siRNA significantly enhanced the cellular sensitivity to certain DNA damaging agents and, concordantly, L13-overexpressing cells demonstrated greater chemoresistance compared to parent cells, suggesting an inverse correlation between L13 expression and chemosensitivity. By using semiquantitative RT-PCR, we analyzed expression of L13 in freshly resected cancer tissue of the stomach, colorectum and liver. Up-regulation of L13 mRNA expression was observed in 10 (28%) of 36 gastric, 19 (41%) of 46 colorectal and 5 (20%) of 25 liver cancer tissue samples compared to adjacent normal tissue samples. We also found that increased expression of the L13 gene correlated with clinical staging in gastric cancers. The results of this study suggest that L13 plays an essential role in the progression of some gastrointestinal malignancies.

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Section: Discussionsupporting

confidence: 82%

Activation of the ribosomal protein L13 gene in human gastrointestinal cancer

Kobayashi

Sasaki²,

Oshima³

et al. 2006

Int J Mol Med

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“…The poly(A)-RNA was size fractionated on a sucrose gradient, and the 28S rRNA was isolated and quantified by optical density at 260 nm. The recovery (65 to 100%) of the 28S rRNA was estimated by inclusion, throughout the purification procedure, of 3H-labeled 28S rRNA (55, developing liver and is similar to that reported for NIH 3T3 fibroblasts (74).…”

Section: Resultssupporting

confidence: 55%

Selective translational control and nonspecific posttranscriptional regulation of ribosomal protein gene expression during development and regeneration of rat liver.

Aloni¹,

Peleg²,

Meyuhas³

1992

Mol. Cell. Biol.

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Mammalian liver development is accompanied by a transition from rapid growth in the fetus to a quiescent state in the adult. However, extensive proliferation can be induced in the adult liver by partial hepatectomy. In this study, we examined the regulation of ribosomal protein (rp) gene expression in the developing and regenerating rat liver. Our results indicate that the translation of rp mRNAs is selectively repressed by about 70%o upon development from fetal to adult life, as illustrated by the decrease in ribosomal loading. In addition, the relative abundance of these mRNAs, like that of several other, but not all, housekeeping mRNAs, declines during development through a posttranscriptional mechanism. When liver cells commence growth following partial hepatectomy, translation of rp mRNAs is resumed to near-maximal capacity, as judged by their very efficient recruitment into polysomes. The concomitant increase in the abundance of rp mRNAs under these circumstances is achieved by a posttranscriptional mechanism. The apparent fluctuations in the translation efficiency of rp mRNAs are accompanied by parallel changes in the expression of the genes encoding the initiation factors eIF-4E and eIF-4A. Our results indicate that selective translational control of rp mRNAs in mammals is not confined to manipulated cells in culture but constitutes an important regulatory mechanism operating in vivo in the course of liver development and regeneration.The biosynthesis of ribosomes in vertebrates is primarily coordinated with the cellular growth status and requires an equimolar accumulation of four rRNA and about 80 different ribosomal protein (rp) molecules. This stoichiometry is maintained by coordinate regulation at various levels of gene expression from transcription to protein turnover (4,31,43,49). Clearly, the translational control of rp mRNAs is the most prevalent regulatory mechanism of vertebrate rp gene expression and operates under a variety of physiological conditions (reference 41 and references therein). Recently, we have shown that the 5'-terminal pyrimidine tract, adjacent to the cap site of all vertebrate rp mRNAs rigorously analyzed thus far, plays a critical role in their coordinate translational control (41).Posttranscriptional control of rp genes, most probably through stability of the corresponding transcripts, has been reported to occur in anucleate Xenopus embryos (62) and in dexamethasone-treated rats (21). In addition, control at the RNA processing level is evident for rpL1 in Xenopus laevis (10). Finally, a balanced accumulation of ribosomal proteins (r-proteins) is also achieved by modulating their turnover, as observed in mouse oocytes (39) and differentiating rat myoblasts (30).The development of rodent liver is associated with progressive decrease of mitotic activity to almost undetectable levels in the adult tissue (reference 46 and references therein). Concomitantly, the hepatocytes acquire differentiated functions and lose others. These developmental changes involve extensive alterations...

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“…Indeed, a recent transcriptome analysis of mouse fibroblasts during the transition from stationary to growth phase found almost no change in the levels of RP mRNAs (19), although there is a substantial increase in the rate of RP synthesis (55).…”

Section: Fig 8 Neithermentioning

confidence: 99%

Transcriptional Elements Involved in the Repression of Ribosomal Protein Synthesis

Nierras

Warner

1999

Molecular and Cellular Biology

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103

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The ribosomal proteins (RPs) of Saccharomyces cerevisiae are encoded by 137 genes that are among the most transcriptionally active in the genome. These genes are coordinately regulated: a shift up in temperature leads to a rapid, but temporary, decline in RP mRNA levels. A defect in any part of the secretory pathway leads to greatly reduced ribosome synthesis, including the rapid loss of RP mRNA. Here we demonstrate that the loss of RP mRNA is due to the rapid transcriptional silencing of the RP genes, coupled to the naturally short lifetime of their transcripts. The data suggest further that a global inhibition of polymerase II transcription leads to overestimates of the stability of individual mRNAs. The transcription of most RP genes is activated by two Rap1p binding sites, 250 to 400 bp upstream from the initiation of transcription. Rap1p is both an activator and a silencer of transcription. The swapping of promoters between RPL30 and ACT1 or GAL1 demonstrated that the Rap1p binding sites of RPL30 are sufficient to silence the transcription of ACT1 in response to a defect in the secretory pathway. Sir3p and Sir4p, implicated in the Rap1p-mediated repression of silent mating type genes and of telomere-proximal genes, do not influence such silencing of RP genes. Sir2p, implicated in the silencing both of the silent mating type genes and of genes within the ribosomal DNA locus, does not influence the repression of either RP or rRNA genes. Surprisingly, the 180-bp sequence of RPL30 that lies between the Rap1p sites and the transcription initiation site is also sufficient to silence the Gal4p-driven transcription in response to a defect in the secretory pathway, by a mechanism that requires the silencing region of Rap1p. We conclude that for Rap1p to activate the transcription of an RP gene it must bind to upstream sequences; yet for Rap1p to repress the transcription of an RP gene it need not bind to the gene directly. Thus, the cell has evolved a two-pronged approach to effect the rapid extinction of RP synthesis in response to the stress imposed by a heat shock or by a failure of the secretory pathway. Calculations based on recent transcriptome data and on the half-life of the RP mRNAs suggest that in a rapidly growing cell the transcription of RP mRNAs accounts for nearly 50% of the total transcriptional events initiated by RNA polymerase II. Thus, the sudden silencing of the RP genes must have a dramatic effect on the overall transcriptional economy of the cell.The Saccharomyces cerevisiae cell invests enormous resources in the synthesis of ribosomes. In a rapidly growing cell, the 100 or more rRNA genes are responsible for at least 60% of total transcription (59). The 137 ribosomal protein (RP) genes are among the most active in the genome (57). As a result, the cell has evolved mechanisms that tightly control the synthesis of the components of the ribosome. The 78 RPs are synthesized in nearly equimolar amounts that are matched to the synthesis of rRNA. Furthermore, the synthesis of these components is coo...

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Ribosomal proteins are synthesized preferentially in cells commencing growth

Cited by 69 publications

References 29 publications

Activation of the ribosomal protein L13 gene in human gastrointestinal cancer

Activation of the ribosomal protein L13 gene in human gastrointestinal cancer

Selective translational control and nonspecific posttranscriptional regulation of ribosomal protein gene expression during development and regeneration of rat liver.

Transcriptional Elements Involved in the Repression of Ribosomal Protein Synthesis

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