Regulation of the MDM2-P53 pathway and tumor growth by PICT1 via nucleolar RPL11

Sato, Masato; Kawahara, Kohichi; Nishio, Makoto; Mimori, Koshi; Kogo, Ryunosuke; Hamada, Koichi; Itoh, Bunsho; Wang, Jia; Komatsu, Yukako; Yang, Yong Ryoul; Hikasa, Hiroki; Horie, Yasuo; Yamashita, Takayuki; Kamijo, Takehiko; Zhang, Yanping; Zhu, Yuyan; Prives, Carol; Nakano, Toru; Mak, Tak W.; Sasaki, Takehiko; Maehama, Tomohiko; Mori, Masaki; Suzuki, Akira

doi:10.1038/nm.2392

Cited by 172 publications

(211 citation statements)

References 51 publications

(68 reference statements)

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“…The binding of RPL5 and RPL11 to Hdm2 and the stabilization of p53 have been demonstrated in a number of settings following impairment of ribosome biogenesis (7,15,16,(32)(33)(34)49). Consistent with the role of RPL5 and RPL11 as positive regulators of p53, recent studies have also highlighted their importance as novel tumor suppressors (5,10,50). In agreement with these reports, RPs have been identified as haploinsufficient tumor suppressors in both Drosophila and zebrafish (51)(52)(53)(54).…”

Section: Discussionsupporting

confidence: 55%

Loss of Tumor Suppressor RPL5/RPL11 Does Not Induce Cell Cycle Arrest but Impedes Proliferation Due to Reduced Ribosome Content and Translation Capacity

Teng

Mercer

Hexley

et al. 2013

Molecular and Cellular Biology

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e Humans have evolved elaborate mechanisms to activate p53 in response to insults that lead to cancer, including the binding and inhibition of Hdm2 by the 60S ribosomal proteins (RPs) RPL5 and RPL11. This same mechanism appears to be activated upon impaired ribosome biogenesis, a risk factor for cancer initiation. As loss of RPL5/RPL11 abrogates ribosome biogenesis and protein synthesis to the same extent as loss of other essential 60S RPs, we reasoned the loss of RPL5 and RPL11 would induce a p53-independent cell cycle checkpoint. Unexpectedly, we found that their depletion in primary human lung fibroblasts failed to induce cell cycle arrest but strongly suppressed cell cycle progression. We show that the effects on cell cycle progression stemmed from reduced ribosome content and translational capacity, which suppressed the accumulation of cyclins at the translational level. Thus, unlike other tumor suppressors, RPL5/RPL11 play an essential role in normal cell proliferation, a function cells have evolved to rely on in lieu of a cell cycle checkpoint.

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Section: Discussionsupporting

confidence: 55%

Loss of Tumor Suppressor RPL5/RPL11 Does Not Induce Cell Cycle Arrest but Impedes Proliferation Due to Reduced Ribosome Content and Translation Capacity

Teng

Mercer

Hexley

et al. 2013

Molecular and Cellular Biology

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“…When normal ribosome biogenesis is disrupted, a resulting p53 response is commonly accepted to play a role in the associated disease phenotypes (Lohrum et al, 2003;Dai and Lu, 2004;Jin et al, 2004;Danilova et al, 2008;Jones et al, 2008;Barlow et al, 2010;Duan et al, 2011;Sasaki et al, 2011). To determine whether SDS disease phenotypes are similarly p53 dependent, we evaluated the influence of p53 inactivation on the organogenesis defects induced by Sbds ATG MO injection, using both MO-mediated p53 knockdown and available p53 mutant alleles.…”

Section: Loss Of P53 Does Not Rescue the Sbds Organogenesis Phenotypesmentioning

confidence: 99%

Ribosomal biogenesis genes play an essential and p53-independent role in zebrafish pancreas development

et al. 2012

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SUMMARYMutations in the human Shwachman-Bodian-Diamond syndrome (SBDS) gene cause defective ribosome assembly and are associated with exocrine pancreatic insufficiency, chronic neutropenia and skeletal defects. However, the mechanism underlying these phenotypes remains unclear. Here we show that knockdown of the zebrafish sbds ortholog fully recapitulates the spectrum of developmental abnormalities observed in the human syndrome, and further implicate impaired proliferation of ptf1a-expressing pancreatic progenitor cells as the basis for the observed pancreatic phenotype. It is thought that diseases of ribosome assembly share a p53-dependent mechanism. However, loss of p53 did not rescue the developmental defects associated with loss of zebrafish sbds. To clarify the molecular mechanisms underlying the observed organogenesis defects, we performed transcriptional profiling to identify candidate downstream mediators of the sbds phenotype. Among transcripts displaying differential expression, functional group analysis revealed marked enrichment of genes related to ribosome biogenesis, rRNA processing and translational initiation. Among these, ribosomal protein L3 (rpl3) and pescadillo (pes) were selected for additional analysis. Similar to knockdown of sbds, knockdown or mutation of either rpl3 or pes resulted in impaired expansion of pancreatic progenitor cells. The pancreatic phenotypes observed in rpl3-and pes-deficient embryos were also independent of p53. Together, these data suggest novel p53-independent roles for ribosomal biogenesis genes in zebrafish pancreas development.

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“…It was also described to have functions in embryogenesis and embryonic stem cell survival (Sasaki et al 2011). Alleles from the tame line increased Gltscr2 expression both when comparing the two selection lines and in the F 2 population.…”

Section: Discussionmentioning

confidence: 97%

Genetic Influences on Brain Gene Expression in Rats Selected for Tameness and Aggression

Heyne

Lautenschlaeger²,

Nelson

et al. 2014

Preprint

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Interindividual differences in many behaviors are partly due to genetic differences, but the identification of the genes and variants that influence behavior remains challenging. Here, we studied an F 2 intercross of two outbred lines of rats selected for tame and aggressive behavior toward humans for .64 generations. By using a mapping approach that is able to identify genetic loci segregating within the lines, we identified four times more loci influencing tameness and aggression than by an approach that assumes fixation of causative alleles, suggesting that many causative loci were not driven to fixation by the selection. We used RNA sequencing in 150 F 2 animals to identify hundreds of loci that influence brain gene expression. Several of these loci colocalize with tameness loci and may reflect the same genetic variants. Through analyses of correlations between allele effects on behavior and gene expression, differential expression between the tame and aggressive rat selection lines, and correlations between gene expression and tameness in F 2 animals, we identify the genes Gltscr2, Lgi4, Zfp40, and Slc17a7 as candidate contributors to the strikingly different behavior of the tame and aggressive animals. B EHAVIORAL differences among members of a species are in part due to genetic variation. The identification of the genes and variants that influence behavior remains challenging. In human genome-wide association studies of psychiatric and cognitive traits, the identified loci typically explain only a small fraction of the heritability, i.e., the additive genetic contribution to the trait (Watanabe et al. 2007;Hovatta and Barlow 2008;Deary et al. 2009;Otowa et al. 2009;Calboli et al. 2010;Terracciano et al. 2010;Flint and Munafo 2013;Rietveld et al. 2013;Sokolowska and Hovatta 2013). In experimental crosses in model species, especially between inbred lines, the identified loci (termed quantitative trait loci, QTL), often explain much more of the heritability (Lynch and Walsh 1998). However, in this design the spatial resolution is limited-the QTL are wide and contain many, sometimes hundreds of genes. With the exception of a handful of identified genes with quantitative effects on behavioral traits (Yalcin et al. 2004;Watanabe et al. 2007;McGrath et al. 2009;Bendesky et al. 2012;Goodson et al. 2012), gene identification is particularly difficult for behavioral QTL that often have modest effect sizes (Flint 2003;Willis-Owen and Flint 2006;Wright et al. 2006;Hovatta and Barlow 2008).The causal variants within a QTL can alter the protein sequence encoded by a gene or affect gene expression. Such Musunuru et al. 2010). A few eQTL studies have also recently been carried out to identify candidate genes for behavioral QTL (Hitzemann et al. 2004;De Jong et al. 2011;Saba et al. 2011;Kelly et al. 2012).Here, we studied two lines of rats (Rattus norvegicus) that, starting from one wild population, have been selected for increased tameness and increased aggression toward humans, respectively. These experimental...

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Regulation of the MDM2-P53 pathway and tumor growth by PICT1 via nucleolar RPL11

Cited by 172 publications

References 51 publications

Loss of Tumor Suppressor RPL5/RPL11 Does Not Induce Cell Cycle Arrest but Impedes Proliferation Due to Reduced Ribosome Content and Translation Capacity

Loss of Tumor Suppressor RPL5/RPL11 Does Not Induce Cell Cycle Arrest but Impedes Proliferation Due to Reduced Ribosome Content and Translation Capacity

Ribosomal biogenesis genes play an essential and p53-independent role in zebrafish pancreas development

Genetic Influences on Brain Gene Expression in Rats Selected for Tameness and Aggression

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