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Article: Growth control and ribosomopathies

Teng, Teng / Thomas, George / Mercer, Carol A

Current Opinion in Genetics & Development. 2013 Feb., v. 23, no. 1

2013

Abstract: Ribosome biogenesis and protein synthesis are two of the most energy consuming processes in a growing cell. Moreover, defects in their molecular components can alter the pattern of gene expression [1,2]. Thus it is understandable that cells have ... ...

Abstract	Ribosome biogenesis and protein synthesis are two of the most energy consuming processes in a growing cell. Moreover, defects in their molecular components can alter the pattern of gene expression [1,2]. Thus it is understandable that cells have developed a surveillance system to monitor the status of the translational machinery. Recent discoveries of causative mutations and deletions in genes linked to ribosome biogenesis have defined a group of similar pathologies termed ribosomopathies. Over the past decade, much has been learned regarding the relationship between growth control and ribosome biogenesis. The discovery of extra-ribosomal functions of several ribosome proteins and their regulation of p53 levels has provided a link from ribosome impairment to cell cycle regulation. Yet, evidence suggesting p53 and/or Hdm2 independent pathways also exists. In this review, we summarize recent advances in understanding the mechanisms underlying the pathologies of ribosomopathies and discuss the relationship between ribosome production and tumorigenesis.
Keywords	biogenesis ; carcinogenesis ; cell cycle ; energy ; gene expression regulation ; genes ; monitoring ; mutation ; protein synthesis ; proteins ; ribosomes ; translation (genetics)
Language	English
Dates of publication	2013-02
Size	p. 63-71.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1077312-5
ISSN	1879-0380 ; 0959-437X
ISSN (online)	1879-0380
ISSN	0959-437X
DOI	10.1016/j.gde.2013.02.001
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Growth control and ribosomopathies.

Teng, Teng / Thomas, George / Mercer, Carol A

Current opinion in genetics & development

2013 Volume 23, Issue 1, Page(s) 63–71

Abstract: Ribosome biogenesis and protein synthesis are two of the most energy consuming processes in a growing cell. Moreover, defects in their molecular components can alter the pattern of gene expression. Thus it is understandable that cells have developed a ... ...

Abstract	Ribosome biogenesis and protein synthesis are two of the most energy consuming processes in a growing cell. Moreover, defects in their molecular components can alter the pattern of gene expression. Thus it is understandable that cells have developed a surveillance system to monitor the status of the translational machinery. Recent discoveries of causative mutations and deletions in genes linked to ribosome biogenesis have defined a group of similar pathologies termed ribosomopathies. Over the past decade, much has been learned regarding the relationship between growth control and ribosome biogenesis. The discovery of extra-ribosomal functions of several ribosome proteins and their regulation of p53 levels has provided a link from ribosome impairment to cell cycle regulation. Yet, evidence suggesting p53 and/or Hdm2 independent pathways also exists. In this review, we summarize recent advances in understanding the mechanisms underlying the pathologies of ribosomopathies and discuss the relationship between ribosome production and tumorigenesis.
MeSH term(s)	Animals ; Cell Cycle ; Humans ; Mutation ; Neoplasms/genetics ; Organelle Biogenesis ; Protein Biosynthesis ; Proto-Oncogene Proteins c-mdm2/genetics ; Proto-Oncogene Proteins c-mdm2/metabolism ; RNA, Ribosomal/biosynthesis ; RNA, Ribosomal/genetics ; Ribosomal Proteins/biosynthesis ; Ribosomal Proteins/genetics ; Ribosomes/genetics ; Ribosomes/metabolism ; Ribosomes/pathology ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	RNA, Ribosomal ; Ribosomal Proteins ; Tumor Suppressor Protein p53 ; ribosomal protein L11 ; ribosomal protein L5 ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
Language	English
Publishing date	2013-02
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1077312-5
ISSN	1879-0380 ; 0959-437X
ISSN (online)	1879-0380
ISSN	0959-437X
DOI	10.1016/j.gde.2013.02.001
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Article ; Online: The GST-BHMT assay and related assays for autophagy.

Dennis, Patrick B / Mercer, Carol A

Methods in enzymology

2009 Volume 452, Page(s) 97–118

Abstract: The endpoint of the autophagic process is the breakdown of delivered cytoplasmic cargo in lysosomes. Therefore, assays based on degradation of cargo are of particular interest in that they can measure regulation of the entire autophagic process, ... ...

Abstract	The endpoint of the autophagic process is the breakdown of delivered cytoplasmic cargo in lysosomes. Therefore, assays based on degradation of cargo are of particular interest in that they can measure regulation of the entire autophagic process, including changes in cargo delivery and breakdown in the lytic compartment. Betaine homocysteine methyltransferase (BHMT) is one of many cytosolic proteins found in the mammalian autophagosome, and delivery of BHMT to the lysosome results in its proteolysis to discrete fragments under certain conditions. Making use of these observations, the GST-BHMT assay was developed as an endpoint, cargo-based autophagy assay. Using this assay as a starting point, additional cargo-based assays have been developed with the potential to measure autophagic degradation of specific subcellular compartments. Here we describe the development and validation of these assays.
MeSH term(s)	Autophagy/physiology ; Betaine-Homocysteine S-Methyltransferase/genetics ; Betaine-Homocysteine S-Methyltransferase/metabolism ; Biological Assay/methods ; Cell Line ; Cytosol/metabolism ; Glutathione Transferase/genetics ; Glutathione Transferase/metabolism ; Humans ; Lysosomes/metabolism ; Phagosomes/metabolism ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism
Chemical Substances	Recombinant Fusion Proteins ; Betaine-Homocysteine S-Methyltransferase (EC 2.1.1.5) ; Glutathione Transferase (EC 2.5.1.18)
Language	English
Publishing date	2009
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1557-7988 ; 0076-6879
ISSN (online)	1557-7988
ISSN	0076-6879
DOI	10.1016/S0076-6879(08)03607-0
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Article ; Online: Mitochondrial Complex I Activity Is Required for Maximal Autophagy.

Thomas, Hala Elnakat / Zhang, Yu / Stefely, Jonathan A / Veiga, Sonia R / Thomas, George / Kozma, Sara C / Mercer, Carol A

Cell reports

2018 Volume 24, Issue 9, Page(s) 2404–2417.e8

Abstract: Cells adapt to nutrient and energy deprivation by inducing autophagy, which is regulated by the mammalian target of rapamycin (mTOR) and AMP-activated protein kinases (AMPKs). We found that cell metabolism significantly influences the ability to induce ... ...

Abstract	Cells adapt to nutrient and energy deprivation by inducing autophagy, which is regulated by the mammalian target of rapamycin (mTOR) and AMP-activated protein kinases (AMPKs). We found that cell metabolism significantly influences the ability to induce autophagy, with mitochondrial complex I function being an important factor in the initiation, amplitude, and duration of the response. We show that phenformin or genetic defects in complex I suppressed autophagy induced by mTOR inhibitors, whereas autophagy was enhanced by strategies that increased mitochondrial metabolism. We report that mTOR inhibitors significantly increased select phospholipids and mitochondrial-associated membranes (MAMs) in a complex I-dependent manner. We attribute the complex I autophagy defect to the inability to increase MAMs, limiting phosphatidylserine decarboxylase (PISD) activity and mitochondrial phosphatidylethanolamine (mtPE), which support autophagy. Our data reveal the dynamic and metabolic regulation of autophagy.
MeSH term(s)	Animals ; Autophagy/genetics ; Humans ; Hypoglycemic Agents/pharmacology ; Mitochondria/metabolism ; Phenformin/pharmacology
Chemical Substances	Hypoglycemic Agents ; Phenformin (DD5K7529CE)
Language	English
Publishing date	2018-09-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2018.07.101
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Article ; Online: 5S ribosomal RNA is an essential component of a nascent ribosomal precursor complex that regulates the Hdm2-p53 checkpoint.

Donati, Giulio / Peddigari, Suresh / Mercer, Carol A / Thomas, George

Cell reports

2013 Volume 4, Issue 1, Page(s) 87–98

Abstract: Recently, we demonstrated that RPL5 and RPL11 act in a mutually dependent manner to inhibit Hdm2 and stabilize p53 following impaired ribosome biogenesis. Given that RPL5 and RPL11 form a preribosomal complex with noncoding 5S ribosomal RNA (rRNA) and ... ...

Abstract	Recently, we demonstrated that RPL5 and RPL11 act in a mutually dependent manner to inhibit Hdm2 and stabilize p53 following impaired ribosome biogenesis. Given that RPL5 and RPL11 form a preribosomal complex with noncoding 5S ribosomal RNA (rRNA) and the three have been implicated in the p53 response, we reasoned they may be part of an Hdm2-inhibitory complex. Here, we show that small interfering RNAs directed against 5S rRNA have no effect on total or nascent levels of the noncoding rRNA, though they prevent the reported Hdm4 inhibition of p53. To achieve efficient inhibition of 5S rRNA synthesis, we targeted TFIIIA, a specific RNA polymerase III cofactor, which, like depletion of either RPL5 or RPL11, did not induce p53. Instead, 5S rRNA acts in a dependent manner with RPL5 and RPL11 to inhibit Hdm2 and stabilize p53. Moreover, depletion of any one of the three components abolished the binding of the other two to Hdm2, explaining their common dependence. Finally, we demonstrate that the RPL5/RPL11/5S rRNA preribosomal complex is redirected from assembly into nascent 60S ribosomes to Hdm2 inhibition as a consequence of impaired ribosome biogenesis. Thus, the activation of the Hdm2-inhibitory complex is not a passive but a regulated event, whose potential role in tumor suppression has been recently noted.
MeSH term(s)	Cell Cycle Checkpoints ; Cell Line, Tumor ; Humans ; Proto-Oncogene Proteins c-mdm2/genetics ; Proto-Oncogene Proteins c-mdm2/metabolism ; RNA Precursors/metabolism ; RNA, Ribosomal, 5S/biosynthesis ; RNA, Ribosomal, 5S/genetics ; RNA, Ribosomal, 5S/metabolism ; Ribosomal Proteins/metabolism ; Transcription Factor TFIIIA/genetics ; Transcription Factor TFIIIA/metabolism ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	RNA Precursors ; RNA, Ribosomal, 5S ; Ribosomal Proteins ; Transcription Factor TFIIIA ; Tumor Suppressor Protein p53 ; ribosomal protein L11 ; ribosomal protein L5, human ; MDM2 protein, human (EC 2.3.2.27) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
Language	English
Publishing date	2013-07-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2013.05.045
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Article ; Online: Impaired ribosome biogenesis checkpoint activation induces p53-dependent MCL-1 degradation and MYC-driven lymphoma death.

Domostegui, Ana / Peddigari, Suresh / Mercer, Carol A / Iannizzotto, Flavia / Rodriguez, Marta L / Garcia-Cajide, Marta / Amador, Virginia / Diepstraten, Sarah T / Kelly, Gemma L / Salazar, Ramón / Kozma, Sara C / Kusnadi, Eric P / Kang, Jian / Gentilella, Antonio / Pearson, Richard B / Thomas, George / Pelletier, Joffrey

Blood

2021 Volume 137, Issue 24, Page(s) 3351–3364

Abstract: MYC-driven B-cell lymphomas are addicted to increased levels of ribosome biogenesis (RiBi), offering the potential for therapeutic intervention. However, it is unclear whether inhibition of RiBi suppresses lymphomagenesis by decreasing translational ... ...

Abstract	MYC-driven B-cell lymphomas are addicted to increased levels of ribosome biogenesis (RiBi), offering the potential for therapeutic intervention. However, it is unclear whether inhibition of RiBi suppresses lymphomagenesis by decreasing translational capacity and/or by p53 activation mediated by the impaired RiBi checkpoint (IRBC). Here we generated Eμ-Myc lymphoma cells expressing inducible short hairpin RNAs to either ribosomal protein L7a (RPL7a) or RPL11, the latter an essential component of the IRBC. The loss of either protein reduced RiBi, protein synthesis, and cell proliferation to similar extents. However, only RPL7a depletion induced p53-mediated apoptosis through the selective proteasomal degradation of antiapoptotic MCL-1, indicating the critical role of the IRBC in this mechanism. Strikingly, low concentrations of the US Food and Drug Administration-approved anticancer RNA polymerase I inhibitor Actinomycin D (ActD) dramatically prolonged the survival of mice harboring Trp53+/+;Eμ-Myc but not Trp53-/-;Eμ-Myc lymphomas, which provides a rationale for treating MYC-driven B-cell lymphomas with ActD. Importantly, the molecular effects of ActD on Eμ-Myc cells were recapitulated in human B-cell lymphoma cell lines, highlighting the potential for ActD as a therapeutic avenue for p53 wild-type lymphoma.
MeSH term(s)	Animals ; Cell Cycle Checkpoints/drug effects ; Cell Cycle Checkpoints/genetics ; Cell Line, Tumor ; Dactinomycin/pharmacology ; Lymphoma, B-Cell/drug therapy ; Lymphoma, B-Cell/genetics ; Lymphoma, B-Cell/metabolism ; Male ; Mice ; Myeloid Cell Leukemia Sequence 1 Protein/genetics ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Proteolysis/drug effects ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; RNA, Neoplasm/genetics ; RNA, Neoplasm/metabolism ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Ribosomal Proteins/antagonists & inhibitors ; Ribosomal Proteins/genetics ; Ribosomal Proteins/metabolism ; Ribosomes/genetics ; Ribosomes/metabolism ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Mcl1 protein, mouse ; Myc protein, mouse ; Myeloid Cell Leukemia Sequence 1 Protein ; Proto-Oncogene Proteins c-myc ; RNA, Neoplasm ; RNA, Small Interfering ; Ribosomal Proteins ; Rpl7a protein, mouse ; Trp53 protein, mouse ; Tumor Suppressor Protein p53 ; Dactinomycin (1CC1JFE158)
Language	English
Publishing date	2021-01-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2020007452
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Article ; Online: Loss of Tumor Suppressor RPL5/RPL11 Does Not Induce Cell Cycle Arrest but Impedes Proliferation Due to Reduced Ribosome Content and Translation Capacity

Teng, Teng / Mercer, Carol A. / Hexley, Philip / Thomas, George / Fumagalli, Stefano

Molecular and Cellular Biology. 2013 Dec. 1, v. 33, no. 23 p.4660-4671

2013

Abstract: 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 ... ...

Abstract	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.
Keywords	biogenesis ; cell cycle checkpoints ; cell proliferation ; cyclins ; fibroblasts ; humans ; lungs ; neoplasms ; protein synthesis ; ribosomes ; risk factors
Language	English
Dates of publication	2013-1201
Size	p. 4660-4671.
Publishing place	Taylor & Francis
Document type	Article ; Online
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.01174-13
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy.

Mercer, Carol A / Kaliappan, Alagammai / Dennis, Patrick B

Autophagy

2009 Volume 5, Issue 5, Page(s) 649–662

Abstract: Macroautophagy is an intracellular, vesicle-mediated mechanism for the sequestration and ultimate lysosomal degradation of cytoplasmic proteins, organelles and macromolecules. The macroautophagy process and many of the autophagy-specific (Atg) proteins ... ...

Abstract	Macroautophagy is an intracellular, vesicle-mediated mechanism for the sequestration and ultimate lysosomal degradation of cytoplasmic proteins, organelles and macromolecules. The macroautophagy process and many of the autophagy-specific (Atg) proteins are remarkably well conserved in higher eukaryotes. In yeast, the Atg1 kinase complex includes Atg1, Atg13, Atg17, and at least four other interacting proteins, some of which are phosphorylated in a TOR-dependent manner, placing the Atg1 signaling complex downstream of a major nutrient-sensing pathway. Atg1 orthologs, including mammalian unc-51-like kinase 1 (ULK1), have been identified in higher eukaryotes and have been functionally linked to autophagy. This suggests that other components of the Atg1 complex exist in higher eukaryotes. Recently, a putative human Atg13 ortholog, FLJ20698, was identified by gapped-BLAST analysis. We show here that FLJ20698 (Atg13) is a ULK1-interacting phosphoprotein that is essential for macroautophagy. Furthermore, we identify a novel, human Atg13-interacting protein, FLJ11773, which we have termed Atg101. Atg101 is essential for autophagy and interacts with ULK1 in an Atg13-dependent manner. Additionally, we present evidence that intracellular localization of the ULK1 complex is regulated by nutrient conditions. Finally, we demonstrate that Atg101 stabilizes the expression of Atg13 in the cell, suggesting that Atg101 contributes to Atg13 function by protecting Atg13 from proteasomal degradation. Therefore, the identification of the novel protein, Atg101, and the validation of Atg13 and Atg101 as ULK1-interacting proteins, suggests an Atg1 complex is involved in the induction of macroautophagy in mammalian cells.
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Autophagy ; Autophagy-Related Protein-1 Homolog ; Autophagy-Related Proteins ; Cell Line ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Models, Biological ; Phosphorylation ; Protein Binding ; Protein Interaction Mapping ; Protein Serine-Threonine Kinases/metabolism ; Protein Stability ; Protein-Tyrosine Kinases/metabolism ; Vesicular Transport Proteins/metabolism
Chemical Substances	ATG13 protein, human ; Adaptor Proteins, Signal Transducing ; ATG101 protein, human ; Autophagy-Related Proteins ; Intracellular Signaling Peptides and Proteins ; RB1CC1 protein, human ; Vesicular Transport Proteins ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Autophagy-Related Protein-1 Homolog (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; ULK1 protein, human (EC 2.7.11.1)
Language	English
Publishing date	2009-07-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.4161/auto.5.5.8249
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Article ; Online: Mass spectrometry proteomics reveals a function for mammalian CALCOCO1 in MTOR-regulated selective autophagy.

Stefely, Jonathan A / Zhang, Yu / Freiberger, Elyse C / Kwiecien, Nicholas W / Thomas, Hala Elnakat / Davis, Alexander M / Lowry, Nathaniel D / Vincent, Catherine E / Shishkova, Evgenia / Clark, Nicholas A / Medvedovic, Mario / Coon, Joshua J / Pagliarini, David J / Mercer, Carol A

Autophagy

2020 Volume 16, Issue 12, Page(s) 2219–2237

Abstract: Macroautophagy/autophagy is suppressed by MTOR (mechanistic target of rapamycin kinase) and is an anticancer target under active investigation. Yet, MTOR-regulated autophagy remains incompletely mapped. We used proteomic profiling to identify proteins in ...

Abstract	Macroautophagy/autophagy is suppressed by MTOR (mechanistic target of rapamycin kinase) and is an anticancer target under active investigation. Yet, MTOR-regulated autophagy remains incompletely mapped. We used proteomic profiling to identify proteins in the MTOR-autophagy axis. Wild-type (WT) mouse cell lines and cell lines lacking individual autophagy genes (
MeSH term(s)	Amino Acid Sequence ; Animals ; Autophagy ; Calcium-Binding Proteins/chemistry ; Calcium-Binding Proteins/metabolism ; Conserved Sequence ; Embryo, Mammalian/cytology ; Fibroblasts/metabolism ; HEK293 Cells ; Humans ; MCF-7 Cells ; Mammals/metabolism ; Mass Spectrometry ; Mice ; Microtubule-Associated Proteins/metabolism ; Protein Binding ; Proteomics ; Saccharomyces cerevisiae/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Transcription Factors/chemistry ; Transcription Factors/metabolism
Chemical Substances	Calcium-Binding Proteins ; Calcoco1 protein, mouse ; Map1lc3b protein, mouse ; Microtubule-Associated Proteins ; Transcription Factors ; TOR Serine-Threonine Kinases (EC 2.7.1.1)
Language	English
Publishing date	2020-02-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.1080/15548627.2020.1719746
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Article ; Online: Loss of tumor suppressor RPL5/RPL11 does not induce cell cycle arrest but impedes proliferation due to reduced ribosome content and translation capacity.

Teng, Teng / Mercer, Carol A / Hexley, Philip / Thomas, George / Fumagalli, Stefano

Molecular and cellular biology

2013 Volume 33, Issue 23, Page(s) 4660–4671

Abstract	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.
MeSH term(s)	Cell Cycle Checkpoints ; Cell Line, Tumor ; Cell Proliferation ; Cyclin A2/metabolism ; Cyclin E/metabolism ; Gene Knockdown Techniques ; Humans ; Oncogene Proteins/metabolism ; Protein Biosynthesis ; RNA, Small Interfering/genetics ; Ribosomal Proteins/genetics ; Ribosomal Proteins/metabolism ; Ribosomes/metabolism ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	CCNA2 protein, human ; CCNE1 protein, human ; Cyclin A2 ; Cyclin E ; Oncogene Proteins ; RNA, Small Interfering ; Ribosomal Proteins ; TP53 protein, human ; Tumor Suppressor Protein p53 ; ribosomal protein L11 ; ribosomal protein L5, human
Language	English
Publishing date	2013-09-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.01174-13
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