scholarly journals Distinct signaling by insulin and IGF-1 receptors and their extra- and intracellular domains

2021 ◽  
Vol 118 (17) ◽  
pp. e2019474118
Author(s):  
Hirofumi Nagao ◽  
Weikang Cai ◽  
Nicolai J. Wewer Albrechtsen ◽  
Martin Steger ◽  
Thiago M. Batista ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Membrane Trafficking ◽  
Rho Gtpases ◽  
Cell Cycle Progression ◽  
Biological Effects ◽  
Mammalian Target Of Rapamycin ◽  
Cycle Progression ◽  
Downstream Signaling ◽  
Molecular Signals ◽  
Intracellular Domains

Insulin and insulin-like growth factor 1 (IGF-1) receptors share many downstream signaling pathways but have unique biological effects. To define the molecular signals contributing to these distinct activities, we performed global phosphoproteomics on cells expressing either insulin receptor (IR), IGF-1 receptor (IGF1R), or chimeric IR-IGF1R receptors. We show that IR preferentially stimulates phosphorylations associated with mammalian target of rapamycin complex 1 (mTORC1) and Akt pathways, whereas IGF1R preferentially stimulates phosphorylations on proteins associated with the Ras homolog family of guanosine triphosphate hydrolases (Rho GTPases), and cell cycle progression. There were also major differences in the phosphoproteome between cells expressing IR versus IGF1R in the unstimulated state, including phosphorylation of proteins involved in membrane trafficking, chromatin remodeling, and cell cycle. In cells expressing chimeric IR-IGF1R receptors, these differences in signaling could be mapped to contributions of both the extra- and intracellular domains of these receptors. Thus, despite their high homology, IR and IGF1R preferentially regulate distinct networks of phosphorylation in both the basal and stimulated states, allowing for the unique effects of these hormones on organismal function.

scholarly journals The N-Terminal 24 Amino Acids of the p55 Gamma Regulatory Subunit of Phosphoinositide 3-Kinase Binds Rb and Induces Cell Cycle Arrest

2003 ◽  
Vol 23 (5) ◽  
pp. 1717-1725 ◽  
Author(s):  
Xianmin Xia ◽  
Aiwu Cheng ◽  
Damilola Akinmade ◽  
Anne W. Hamburger
Keyword(s):  
Cell Cycle ◽  
Amino Acid ◽  
Cell Cycle Arrest ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Biological Effects ◽  
Cycle Progression ◽  
Regulatory Subunits ◽  
Cycle Arrest ◽  
Phosphoinositide 3 Kinase

ABSTRACT Although phosphoinositide 3-kinase (PI 3-kinase) is essential for cell cycle progression, the molecular mechanisms that regulate its diverse biological effects are poorly understood. We demonstrate here that Rb, a key regulator of cell cycle progression, associates with p55 kDa (p55α and p55γ) regulatory subunits of PI 3-kinase in vivo and in vitro. Both confocal microscopy and biochemical analysis demonstrated the presence of p55γ in the nucleus. The 24-amino-acid N-terminal end of p55γ, which is unique among PI 3-kinase regulatory subunits, was sufficient to bind Rb. Addition of serum or growth factors to quiescent cells triggered the dissociation of Rb from p55. Ectopic expression of the 24-amino-acid N-terminal end of p55γ inhibited cell cycle progression, as evidenced by induction of cell growth arrest at the G0/G1 phase, inhibition of DNA synthesis, inhibition of cyclin D and cyclin E promoter activity, and changes in the expression of cell cycle-related proteins. The inhibitory effects of the N-terminal end of p55γ on cell cycle progression depended on the presence of functional Rb. These data demonstrate for the first time an association of p55γ with Rb and show that modification of this association can lead to cell cycle arrest.

Novel thiosemicarbazone derivative 17B interferes with the cell cycle progression and induce apoptosis through modulating downstream signaling pathways

Gene Reports ◽  
2020 ◽  
Vol 18 ◽  
pp. 100578 ◽  
Author(s):  
Esra Bozgeyik ◽  
Demet Tasdemir-Kahraman ◽  
Kaifee Arman ◽  
Ibrahim Bozgeyik ◽  
Aysegül Karakucuk-Iyidogan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Signaling Pathways ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Downstream Signaling

scholarly journals Activation of Mammalian Target of Rapamycin Signaling Promotes Cell Cycle Progression and Protects Cells from Apoptosis in Mantle Cell Lymphoma

2006 ◽  
Vol 169 (6) ◽  
pp. 2171-2180 ◽  
Author(s):  
Evangelia Peponi ◽  
Elias Drakos ◽  
Guadalupe Reyes ◽  
Vasiliki Leventaki ◽  
George Z. Rassidakis ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Mantle Cell Lymphoma ◽  
Cell Cycle Progression ◽  
Cell Lymphoma ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Cycle Progression ◽  
Mantle Cell

scholarly journals Rho GTPases and their effector proteins

2000 ◽  
Vol 348 (2) ◽  
pp. 241-255 ◽  
Author(s):  
Anne L. BISHOP ◽  
Alan HALL
Keyword(s):  
Rho Gtpases ◽  
Cell Cycle Progression ◽  
Biological Effects ◽  
Effector Proteins ◽  
Actin Dynamics ◽  
Filamentous Actin ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Specific Effector ◽  
Rho Family

Rho GTPases are molecular switches that regulate many essential cellular processes, including actin dynamics, gene transcription, cell-cycle progression and cell adhesion. About 30 potential effector proteins have been identified that interact with members of the Rho family, but it is still unclear which of these are responsible for the diverse biological effects of Rho GTPases. This review will discuss how Rho GTPases physically interact with, and regulate the activity of, multiple effector proteins and how specific effector proteins contribute to cellular responses. To date most progress has been made in the cytoskeleton field, and several biochemical links have now been established between GTPases and the assembly of filamentous actin. The main focus of this review will be Rho, Rac and Cdc42, the three best characterized mammalian Rho GTPases, though the genetic analysis of Rho GTPases in lower eukaryotes is making increasingly important contributions to this field.

scholarly journals Dynamic, Rho1p-dependent localization of Pkc1p to sites of polarized growth

2000 ◽  
Vol 113 (15) ◽  
pp. 2685-2693 ◽  
Author(s):  
P.D. Andrews ◽  
M.J. Stark
Keyword(s):  
Cell Cycle ◽  
Cell Wall ◽  
Membrane Trafficking ◽  
Rho Gtpases ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Wall Stress ◽  
Live Cells ◽  
Polarized Growth ◽  
Temporal Localization

In eukaryotes, the Rho GTPases and their effectors are key regulators of the actin cytoskeleton, membrane trafficking and secretion, cell growth, cell cycle progression and cytokinesis. Budding yeast Pkc1p, a protein kinase C-like enzyme involved in cell wall biosynthesis and cytoskeletal polarity, is structurally and functionally related to the Rho-associated kinases (PRK/ROCK) of mammalian cells. In this study, localization of Pkc1p was monitored in live cells using a GFP fusion (Pkc1p-GFP). Pkc1p-GFP showed dynamic spatial and temporal localization at sites of polarized growth. Early in the cell cycle, Pkc1p-GFP was found at the pre-bud site and bud tips, becoming delocalized as the cell progressed further and finally relocalizing around the mother-daughter bud neck in an incomplete ring, which persisted until cell separation. Bud localization was actin-dependent but stability of Pkc1p-GFP at the neck was actin-independent, although localization at both sites required functional Rho1p. In addition, Pkc1p-GFP showed rapid relocalization after cell wall damage. These results suggest that the roles of Pkc1p in both polarized growth and the response to cell wall stress are mediated by dynamic changes in its localization, and suggest an additional potential role in cytokinesis.

scholarly journals Prenylated Flavonoids fromMorus albaL. Cause Inhibition of G1/S Transition in THP-1 Human Leukemia Cells and Prevent the Lipopolysaccharide-Induced Inflammatory Response

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Peter Kollar ◽  
Tomáš Bárta ◽  
Jan Hošek ◽  
Karel Souček ◽  
Veronika Müller Závalová ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Inflammatory Response ◽  
Cell Cycle Progression ◽  
Human Cancer ◽  
Biological Effects ◽  
Cell Types ◽  
Human Leukemia ◽  
Cycle Progression ◽  
Prenylated Flavonoids ◽  
Anti Inflammatory

Morus albaL. (MA) is a natural source of many compounds with different biological effects. It has been described to possess anti-inflammatory, antioxidant, and hepatoprotective activities. The aim of this study was to evaluate cytotoxicity of three flavonoids isolated from MA (kuwanon E, cudraflavone B, and4′-O-methylkuwanon E) and to determine their effects on proliferation of THP-1 cells, and on cell cycle progression of cancer cells. Anti-inflammatory effects were also determined for all three given flavonoids. Methods used in the study included quantification of cells by hemocytometer and WST-1 assays, flow cytometry, western blotting, ELISA, and zymography. From the three compounds tested, cudraflavone B showed the strongest effects on cell cycle progression and viability of tumor and/or immortalized cells and also on inflammatory response of macrophage-like cells. Kuwanon E and4′-O-methylkuwanon E exerted more sophisticated rather than direct toxic effect on used cell types. Our data indicate that mechanisms different from stress-related or apoptotic signaling pathways are involved in the action of these compounds. Although further studies are required to precisely define the mechanisms of MA flavonoid action in human cancer and macrophage-like cells, here we demonstrate their effects combining antiproliferative and anti-inflammatory activities, respectively.

scholarly journals HCF-1 promotes cell cycle progression by regulating the expression of CDC42

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Pan Xiang ◽  
Fei Li ◽  
Zhihua Ma ◽  
Jiping Yue ◽  
Cailing Lu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Chromosome Segregation ◽  
Rho Gtpases ◽  
Cell Cycle Progression ◽  
Eukaryotic Cell ◽  
Transcription Start ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Host Cell Factor 1 ◽  
Regulation Mode

Abstract The eukaryotic cell cycle involves a highly orchestrated series of events in which the cellular genome is replicated during a synthesis (S) phase and each of the two resulting copies are segregated properly during mitosis (M). Host cell factor-1 (HCF-1) is a transcriptional co-regulator that is essential for and has been implicated in basic cellular processes, such as transcriptional regulation and cell cycle progression. Although a series of HCF-1 transcriptional targets have been identified, few functional clues have been provided, especially for chromosome segregation. Our results showed that HCF-1 activated CDC42 expression by binding to the −881 to −575 region upstream of the CDC42 transcription start site, and the regulation of CDC42 expression by HCF-1 was correlated with cell cycle progression. The overexpression of a spontaneously cycling and constitutively active CDC42 mutant (CDC42F28L) rescued G1 phase delay and multinucleate defects in mitosis upon the loss of HCF-1. Therefore, these results establish that HCF-1 ensures proper cell cycle progression by regulating the expression of CDC42, which indicates a possible mechanism of cell cycle coordination and the regulation mode of typical Rho GTPases.

scholarly journals RhoE Inhibits Cell Cycle Progression and Ras-Induced Transformation

2004 ◽  
Vol 24 (18) ◽  
pp. 7829-7840 ◽  
Author(s):  
Priam Villalonga ◽  
Rosa M. Guasch ◽  
Kirsi Riento ◽  
Anne J. Ridley
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cyclin D1 ◽  
Rho Gtpases ◽  
Cell Cycle Progression ◽  
Inhibitory Effect ◽  
Cell Cycle Checkpoint ◽  
Actin Stress Fiber ◽  
Cycle Progression ◽  
Adenovirus E1a

ABSTRACT Rho GTPases are major regulators of cytoskeletal dynamics, but they also affect cell proliferation, transformation, and oncogenesis. RhoE, a member of the Rnd subfamily that does not detectably hydrolyze GTP, inhibits RhoA/ROCK signaling to promote actin stress fiber and focal adhesion disassembly. We have generated fibroblasts with inducible RhoE expression to investigate the role of RhoE in cell proliferation. RhoE expression induced a loss of stress fibers and cell rounding, but these effects were only transient. RhoE induction inhibited cell proliferation and serum-induced S-phase entry. Neither ROCK nor RhoA inhibition accounted for this response. Consistent with its inhibitory effect on cell cycle progression, RhoE expression was induced by cisplatin, a DNA damage-inducing agent. RhoE-expressing cells failed to accumulate cyclin D1 or p21cip1 protein or to activate E2F-regulated genes in response to serum, although ERK, PI3-K/Akt, FAK, Rac, and cyclin D1 transcription was activated normally. The expression of proteins that bypass the retinoblastoma (pRb) family cell cycle checkpoint, including human papillomavirus E7, adenovirus E1A, and cyclin E, rescued cell cycle progression in RhoE-expressing cells. RhoE also inhibited Ras- and Raf-induced fibroblast transformation. These results indicate that RhoE inhibits cell cycle progression upstream of the pRb checkpoint.

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