scholarly journals A prion accelerates proliferation at the expense of lifespan

2020 ◽  
Author(s):  
David M. Garcia ◽  
Edgar A. Campbell ◽  
Christopher M. Jakobson ◽  
Mitsuhiro Tsuchiya ◽  
Acadia DiNardo ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Cell Growth ◽  
Cell Size ◽  
Functional Role ◽  
Growth And Survival ◽  
Pseudouridine Synthase ◽  
Epigenetic State ◽  
Altered Protein ◽  
Fluctuating Environments ◽  
The Cost

ABSTRACTOrganisms often commit to one of two strategies: living fast and dying young or living slow and dying old. In fluctuating environments, however, switching between these two strategies could be advantageous. Lifespan is often inversely correlated with cell size and proliferation, which are both limited by protein synthesis. Here we report that a highly conserved RNA-modifying enzyme, the pseudouridine synthase Pus4/TruB, can act as a prion, endowing yeast with greater proliferation rates at the cost of a shortened lifespan. Cells harboring the prion can grow larger and exhibit altered protein synthesis. This epigenetic state, [BIG+] (better in growth), allows cells to heritably yet reversibly alter their translational program, leading to the differential expression of hundreds of proteins, including many that regulate proliferation and aging. Our data reveal a functional role for aggregation of RNA-modifying enzymes in driving heritable epigenetic states that transform cell growth and survival.

scholarly journals A prion accelerates proliferation at the expense of lifespan

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
David M Garcia ◽  
Edgar A Campbell ◽  
Christopher M Jakobson ◽  
Mitsuhiro Tsuchiya ◽  
Ethan A Shaw ◽  
...  
Keyword(s):  
Cell Size ◽  
Growth Strategies ◽  
Growth And Survival ◽  
Regulatory Pathways ◽  
Pseudouridine Synthase ◽  
Epigenetic State ◽  
Altered Protein ◽  
Trade Offs ◽  
Fluctuating Environments ◽  
The Cost

In fluctuating environments, switching between different growth strategies, such as those affecting cell size and proliferation, can be advantageous to an organism. Trade-offs arise, however. Mechanisms that aberrantly increase cell size or proliferation—such as mutations or chemicals that interfere with growth regulatory pathways—can also shorten lifespan. Here we report a natural example of how the interplay between growth and lifespan can be epigenetically controlled. We find that a highly conserved RNA-modifying enzyme, the pseudouridine synthase Pus4/TruB, can act as a prion, endowing yeast with greater proliferation rates at the cost of a shortened lifespan. Cells harboring the prion grow larger and exhibit altered protein synthesis. This epigenetic state, [BIG+] (better in growth), allows cells to heritably yet reversibly alter their translational program, leading to the differential synthesis of dozens of proteins, including many that regulate proliferation and aging. Our data reveal a new role for prion-based control of an RNA-modifying enzyme in driving heritable epigenetic states that transform cell growth and survival.

scholarly journals Pim and Akt oncogenes are independent regulators of hematopoietic cell growth and survival

Blood ◽  
2005 ◽  
Vol 105 (11) ◽  
pp. 4477-4483 ◽  
Author(s):  
Peter S. Hammerman ◽  
Casey J. Fox ◽  
Morris J. Birnbaum ◽  
Craig B. Thompson
Keyword(s):  
Cell Growth ◽  
Cell Size ◽  
Ectopic Expression ◽  
Hematopoietic Cells ◽  
Tumor Formation ◽  
Hematopoietic Cell ◽  
Leukemic Cells ◽  
Growth And Survival ◽  
Critical Components ◽  
Cell Growth And Survival

Abstract The Akt kinases promote hematopoietic cell growth and accumulation through phosphorylation of apoptotic effectors and stimulation of mTOR-dependent translation. In Akt-transformed leukemic cells, tumor growth can be inhibited by the mTOR inhibitor rapamycin, and clinical trials of rapamycin analogs for the treatment of leukemia are under way. Surprisingly, nontransformed hematopoietic cells can grow and proliferate in the presence of rapamycin. Here, we show that Pim-2 is required to confer rapamycin resistance. Primary hematopoietic cells from Pim-2– and Pim-1/Pim-2–deficient animals failed to accumulate and underwent apoptosis in the presence of rapamycin. Although animals deficient in Akt-1 or Pim-1/Pim-2 are viable, few animals with a compound deletion survived development, and those that were born had severe anemia. Primary hematopoietic cells from Akt-1/Pim-1/Pim-2–deficient animals displayed marked impairments in cell growth and survival. Conversely, ectopic expression of either Pim-2 or Akt-1 induced increased cell size and apoptotic resistance. However, though the effects of ectopic Akt-1 were reversed by rapamycin or a nonphosphorylatable form of 4EBP-1, those of Pim-2 were not. Coexpression of the transgenes in mice led to additive increases in cell size and survival and predisposed animals to rapid tumor formation. Together, these data indicate that Pim-2 and Akt-1 are critical components of overlapping but independent pathways, either of which is sufficient to promote the growth and survival of nontransformed hematopoietic cells.

scholarly journals A functional role for Smad7 in sustaining colon cancer cell growth and survival

2014 ◽  
Vol 5 (2) ◽  
pp. e1073-e1073 ◽  
Author(s):  
C Stolfi ◽  
V De Simone ◽  
A Colantoni ◽  
E Franzè ◽  
E Ribichini ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cell Growth ◽  
Cancer Cell ◽  
Functional Role ◽  
Colon Cancer Cell ◽  
Cancer Cell Growth ◽  
Growth And Survival ◽  
Cell Growth And Survival

scholarly journals Pseudouridine-FreeEscherichia coliRibosomes

2017 ◽  
Vol 200 (4) ◽  
Author(s):  
Michael O'Connor ◽  
Margus Leppik ◽  
Jaanus Remme
Keyword(s):  
Cell Growth ◽  
Functional Role ◽  
Ribosome Biogenesis ◽  
Content Type ◽  
E Coli ◽  
Pseudouridine Synthase ◽  
Domains Of Life ◽  
And Function ◽  
Critical Regions ◽  
Dependent Mechanism

ABSTRACTPseudouridine (Ψ) is present at conserved, functionally important regions in the ribosomal RNAs (rRNAs) from all three domains of life. Little, however, is known about the functions of Ψ modifications in bacterial ribosomes. AnEscherichia colistrain has been constructed in which all seven rRNA Ψ synthases have been inactivated and whose ribosomes are devoid of all Ψs. Surprisingly, this strain displays only minor defects in ribosome biogenesis and function, and cell growth is only modestly affected. This is in contrast to a strong requirement for Ψ in eukaryotic ribosomes and suggests divergent roles for rRNA Ψ modifications in these two domains.IMPORTANCEPseudouridine (Ψ) is the most abundant posttranscriptional modification in RNAs. In the ribosome, Ψ modifications are typically located at conserved, critical regions, suggesting they play an important functional role. In eukarya and archaea, rRNAs are modified by a single pseudouridine synthase (PUS) enzyme, targeted to rRNA via a snoRNA-dependent mechanism, while bacteria use multiple stand-alone PUS enzymes. Disruption of Ψ modification of rRNA in eukarya seriously impairs ribosome function and cell growth. We have constructed anE. colimultiple deletion strain lacking all Ψ modifications in rRNA. In contrast to the equivalent eukaryotic mutants, theE. colistrain is only modestly affected in growth, decoding, and ribosome biogenesis, indicating a differential requirement for Ψ modifications in these two domains.

scholarly journals Interferons modulate mitogen-induced protein synthesis in airway smooth muscle

2010 ◽  
Vol 299 (1) ◽  
pp. L25-L35 ◽  
Author(s):  
Elena A. Goncharova ◽  
Poay N. Lim ◽  
Amelia Chisolm ◽  
Homer W. Fogle ◽  
Jerome H. Taylor ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Smooth Muscle ◽  
Cell Growth ◽  
Protein Expression ◽  
Cell Size ◽  
Airway Smooth Muscle ◽  
Contractile Protein ◽  
Combined Effects ◽  
Cytosolic Protein ◽  
Ifn Γ

Severe asthma is characterized by increased airway smooth muscle (ASM) mass due, in part, to ASM cell growth and contractile protein expression associated with increased protein synthesis. Little is known regarding the combined effects of mitogens and interferons on ASM cytosolic protein synthesis. We demonstrate that human ASM mitogens including PDGF, EGF, and thrombin stimulate protein synthesis. Surprisingly, pleiotropic cytokines IFN-β and IFN-γ, which inhibit ASM proliferation, also increased cytosolic protein content in ASM cells. Thus IFN-β alone significantly increased protein synthesis by 1.62 ± 0.09-fold that was further enhanced by EGF to 2.52 ± 0.17-fold. IFN-γ alone also stimulated protein synthesis by 1.91 ± 0.15-fold; treatment of cells with PDGF, EGF, and thrombin in the presence of IFN-γ stimulated protein synthesis by 2.24 ± 0.3-, 1.25 ± 0.17-, and 2.67 ± 0.34-fold, respectively, compared with growth factors alone. The mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) inhibition with rapamycin inhibited IFN- and EGF-induced protein synthesis, suggesting that IFN-induced protein synthesis is modulated by mTOR/S6K1 activation. Furthermore, overexpression of tumor suppressor protein tuberous sclerosis complex 2 (TSC2), which is an upstream negative regulator of mTOR/S6K1 signaling, also inhibited mitogen-induced protein synthesis in ASM cells. IFN-β and IFN-γ stimulated miR143/145 microRNA expression and increased SM α-actin accumulation but had little effect on ASM cell size. In contrast, EGF increased ASM cell size but had little effect on miR143/145 expression. Our data demonstrate that both IFNs and mitogens stimulate protein synthesis but have differential effects on cell size and contractile protein expression and suggest that combined effects of IFNs and mitogens may contribute to ASM cell growth, contractile protein expression, and ASM remodeling in asthma.

Altered protein synthesis during in situ oat leaf senescence

1990 ◽  
Vol 80 (4) ◽  
pp. 619-623 ◽  
Author(s):  
Louise Lalonde ◽  
Rajinder S. Dhindsa
Keyword(s):  
Protein Synthesis ◽  
Leaf Senescence ◽  
Altered Protein

scholarly journals Regulation of mRNA Translation by Hormone Receptors in Breast and Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3254
Author(s):  
Jianling Xie ◽  
Eric P. Kusnadi ◽  
Luc Furic ◽  
Luke A. Selth
Keyword(s):  
Prostate Cancer ◽  
Protein Synthesis ◽  
Causes Of Death ◽  
Hormone Receptors ◽  
Mrna Translation ◽  
Estrogen Receptor Α ◽  
Growth And Survival ◽  
Cancer Types ◽  
Breast And Prostate Cancer ◽  
Hormone Signalling

Breast and prostate cancer are the second and third leading causes of death amongst all cancer types, respectively. Pathogenesis of these malignancies is characterised by dysregulation of sex hormone signalling pathways, mediated by the estrogen receptor-α (ER) in breast cancer and androgen receptor (AR) in prostate cancer. ER and AR are transcription factors whose aberrant function drives oncogenic transcriptional programs to promote cancer growth and progression. While ER/AR are known to stimulate cell growth and survival by modulating gene transcription, emerging findings indicate that their effects in neoplasia are also mediated by dysregulation of protein synthesis (i.e., mRNA translation). This suggests that ER/AR can coordinately perturb both transcriptional and translational programs, resulting in the establishment of proteomes that promote malignancy. In this review, we will discuss relatively understudied aspects of ER and AR activity in regulating protein synthesis as well as the potential of targeting mRNA translation in breast and prostate cancer.

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