Regulation of protein synthesis in human diploid fibroblasts: Reduced initiation efficiency in resting cultures

Meedel, Thomas H.; Levine, Elliot M.

doi:10.1002/jcp.1040940212

Cited by 33 publications

(15 citation statements)

References 35 publications

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“…We observed a dramatic decrease in levels of critical translation factors during cellular transition from dividing state to quiescence, suggesting that their cleavage by proteasomes can contribute to a well-known phenomenon of translational attenuation in resting/quiescent cells 42. A broader question is how the IPDP regulates levels of different IPSes at distinct stages of cell life.…”

Section: Discussionmentioning

confidence: 86%

Proteasomes Can Degrade a Significant Proportion of Cellular Proteins Independent of Ubiquitination

Baugh

Viktorova

Pilipenko

2009

Journal of Molecular Biology

183

175

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Summary The critical role of the ubiquitin-26S proteasome system in regulation of protein homeostasis in eukaryotes is well established. In contrast, the impact of the ubiquitin-independent proteolytic activity of proteasomes is poorly understood. Through biochemical analysis of mammalian lysates, we find that the 20S proteasome, latent in peptide hydrolysis, specifically cleaves more than 20% of all cellular proteins. Thirty intrinsic proteasome substrates (IPSes) were identified and in vitro studies of their processing revealed that cleavage occurs at disordered regions, generating stable products encompassing structured domains. The mechanism of IPS recognition is remarkably conserved in the eukaryotic kingdom, as mammalian and yeast 20S proteasomes exhibit the same target specificity. Further, 26S proteasomes specifically recognize and cleave IPSes at similar sites, independent of ubiquitination, suggesting that disordered regions likely constitute the universal structural signal for IPS proteolysis by proteasomes. Finally, we show that proteasomes contribute to physiological regulation of IPS levels in living cells and the inactivation of ubiquitin-activating enzyme E1 does not prevent IPS degradation. Collectively, these findings suggest a significant contribution of the ubiquitin-independent proteasome degradation pathway to the regulation of protein homeostasis in eukaryotes.

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Section: Discussionmentioning

confidence: 86%

Proteasomes Can Degrade a Significant Proportion of Cellular Proteins Independent of Ubiquitination

Baugh

Viktorova

Pilipenko

2009

Journal of Molecular Biology

183

175

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“…A number of additional parallels can be drawn between senescence and the Go state produced in young cells by confluence or serum deprivation. Similarities between these two noncycling states have been demonstrated with respect to decreases in the template activity of the nuclei (Rossini et al, 1976), decreased RNA and protein synthesis (Evans et al, 1978;Meedel and Levine, 1978;Macieira-Coelho et al, 1966), increases in protein degradation (Castor, 1977;Bradley et al, 1976), and increases in mean cell volumes (Mitsui and Schneider, 1976). Furthermore, Rabinovitch and Norwood (1980) and Stein and Yanishevsky (1981) have shown that senescent HDFL cells and quiescent (serumdeprived) cells at low passage levels behave in a similar manner upon fusion with cycling HDFL cells.…”

mentioning

confidence: 91%

Evidence for differences in the mechanism of cell cycle arrest between senescent and serum‐deprived human fibroblasts: Heterokaryon and metabolic inhibitor studies

Burmer

Rabinovitch

Norwood

1984

Journal Cellular Physiology

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It has previously been shown that serum-deprived, early passage quiescent human diploid fibroblastlike (HDFL) cells are able to inhibit cycling cells from entry into DNA synthesis upon cell fusion. We have found that the degree of inhibition of DNA synthesis in the heterokaryon correlates with the duration of serum deprivation, which is consistent with the suggestion that serum-deprived cells may enter progressively deeper stages of G0 as they increase their time in quiescence. In contrast to fusions with senescent cells, in heterokaryons between serum-deprived early passage and cycling young cells transient inhibition of protein synthesis with cycloheximide or inhibition of RNA synthesis with 5-6-dichloro-1-beta-D-ribofuranosyl benzimidazole (DRB) did not stimulate nuclear [3H]-thymidine incorporation. These results suggest that differences may exist in the mechanisms responsible for inhibiting cell cycle progression in senescent vs early passage quiescent HDFL cells.

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“…Serum factor depletion (Meedel and Levine, 1978), heat shock (Scharf and Nover, 1982) and hyperosmolarity (Kruppa and Martini, 1978;Martini and Kruppa, 1979) on the other hand reduce protein synthetic activity by affecting initiation rates as well as reducing the fraction of mRNAs in polysomes. These treatments lead in addition to a massive dephosphorylation of protein S6 (Kruppa and Martini, 1978;Scharf and Nover, 1982).…”

Section: Introductionmentioning

confidence: 99%

Differential kinetics of changes in the state of phosphorylation of ribosomal protein S6 and in the rate of protein synthesis in MPC 11 cells during tonicity shifts.

Kruppa¹,

Clemens²

1984

The EMBO Journal

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Mouse myeloma (MPC 11) cells respond rapidly to hypertonic conditions by shutting down protein synthesis at the level of polypeptide chain initiation. Translational activity recovers equally quickly upon a return to isotonicity. Disaggregation and reformation of polysomes occur in parallel to the changes in protein synthesis. Ribosomal protein S6 becomes dephosphorylated under hypertonic conditions and rephosphorylated when isotonic conditions are restored. The kinetics with which these changes occur are, however, too slow to account for the changes in protein synthesis. Treatment of the cells with a low concentration of cycloheximide allows reformation of polysomes under hypertonic conditions; conversely, puromycin prevents the restoration of polysomes which otherwise occurs on return to isotonicity. Neither inhibitor prevents the changes in S6 phosphorylation resulting from the tonicity shifts. We conclude that the overall extent of phosphorylation of S6 neither regulates nor is determined by the rate of protein synthesis and is not obligatorily related to the proportion of ribosomes in polysomes.

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Regulation of protein synthesis in human diploid fibroblasts: Reduced initiation efficiency in resting cultures

Cited by 33 publications

References 35 publications

Proteasomes Can Degrade a Significant Proportion of Cellular Proteins Independent of Ubiquitination

Proteasomes Can Degrade a Significant Proportion of Cellular Proteins Independent of Ubiquitination

Evidence for differences in the mechanism of cell cycle arrest between senescent and serum‐deprived human fibroblasts: Heterokaryon and metabolic inhibitor studies

Differential kinetics of changes in the state of phosphorylation of ribosomal protein S6 and in the rate of protein synthesis in MPC 11 cells during tonicity shifts.

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