2005
DOI: 10.1101/gad.359305
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Inactivation of S6 ribosomal protein gene in T lymphocytes activates a p53-dependent checkpoint response

Abstract: Ribosome biogenesis has been associated with regulation of cell growth and cell division, but the molecular mechanisms that integrate the effect of ribosome biogenesis on these processes in mammalian cells remain unknown. To study the effect of impaired ribosome functions in vivo, we conditionally deleted one or two alleles of the 40S ribosomal protein S6 gene in T cells in the mouse. While complete deletion of S6 abrogated T-cell development, hemizygous expression did not have any effect on T-cell maturation … Show more

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Cited by 188 publications
(132 citation statements)
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“…18 To investigate this apparent novel cell cycle checkpoint, the S6 ribosomal protein gene was conditionally deleted in the T-cell lineage using CD4-Cre transgenic mice. While the deletion of both alleles of the S6 gene resulted in the complete block in Tcell development (more than 50% of the mice lacked a thymus and the remainder contained 100-fold fewer T cells), deletion of only a single allele of S6 did not perturb thymic development.…”
Section: Ribosomal Biogenesis Checkpoint Is P53 Dependentmentioning
confidence: 99%
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“…18 To investigate this apparent novel cell cycle checkpoint, the S6 ribosomal protein gene was conditionally deleted in the T-cell lineage using CD4-Cre transgenic mice. While the deletion of both alleles of the S6 gene resulted in the complete block in Tcell development (more than 50% of the mice lacked a thymus and the remainder contained 100-fold fewer T cells), deletion of only a single allele of S6 did not perturb thymic development.…”
Section: Ribosomal Biogenesis Checkpoint Is P53 Dependentmentioning
confidence: 99%
“…Consistent with this possibility, Volarevic and co-workers reported that S6-haploinsufficiency in stimulated T lymphocytes did not activate key DNA damage repair proteins implying that DNA damage is not responsible for the p53-dependent checkpoint. 18 The absence of a DNA damage response may point to the possible involvement of Arf, which is harbored within the nucleolus, and can activate p53 independently of the Atm/Atr signaling pathway (Figure 1). Perturbations in ribosome assembly could cause nucleolar alterations that 'unleash' Arf to target Mdm2, indirectly leading to functional p53 and cell cycle arrest and/or death.…”
Section: How Is the Checkpoint Sensed?mentioning
confidence: 99%
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“…Furthermore, it was shown that conditional knockout of rpS6 in the thymus causes failure of T-cell development (Sulic et al, 2005) because of the activation of a p53-dependent checkpoint rather than a defect in protein translation. Another report showed that the activation of p53 by rpS6 depletion resulted in the construction of a rpL11-Mdm2-p53 circuit dependent upon 5 0 -TOP mRNA translation (Fumagalli et al, 2009).…”
Section: Introductionmentioning
confidence: 99%
“…In this context, an impaired ribosome function through conditional knock-out of the 40S ribosomal protein S6 in T cells triggered defects in the fidelity of the translational machinery and consequently activated some p53-dependent checkpoint pathways to prevent aberrant cell division [42]. Which proteins would not be properly translated because of defects in tRNA modifications upon Elongator deficiency and how translational infidelity triggers selected p53 pathways remain unclear issues.…”
Section: Discussionmentioning
confidence: 99%