Signaling Pathways that Control Cell Proliferation
01 Mar 2013-Cold Spring Harbor Perspectives in Biology (Cold Spring Harbor Laboratory Press)-Vol. 5, Iss: 3
TL;DR: Both mitogenic and antiproliferative signals exert their effects on cell proliferation through the transcriptional regulation and ubiquitin-dependent degradation of cyclins and CDK inhibitors.
Abstract: Cells decide to proliferate or remain quiescent using signaling pathways that link information about the cellular environment to the G1 phase of the cell cycle. Progression through G1 phase is controlled by pRB proteins, which function to repress the activity of E2F transcription factors in cells exiting mitosis and in quiescent cells. Phosphorylation of pRB proteins by the G1 cyclin-dependent kinases (CDKs) releases E2F factors, promoting the transition to S phase. CDK activity is primarily regulated by the binding of CDK catalytic subunits to cyclin partners and CDK inhibitors. Consequently, both mitogenic and antiproliferative signals exert their effects on cell proliferation through the transcriptional regulation and ubiquitin-dependent degradation of cyclins and CDK inhibitors.
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TL;DR: An examination of the PI3K-Akt and Ras-ERK pathways illustrates how such alterations dysregulate signaling in cancer and produce many of the characteristic features of tumor cells.
Abstract: Cancer is driven by genetic and epigenetic alterations that allow cells to overproliferate and escape mechanisms that normally control their survival and migration. Many of these alterations map to signaling pathways that control cell growth and division, cell death, cell fate, and cell motility, and can be placed in the context of distortions of wider signaling networks that fuel cancer progression, such as changes in the tumor microenvironment, angiogenesis, and inflammation. Mutations that convert cellular proto-oncogenes to oncogenes can cause hyperactivation of these signaling pathways, whereas inactivation of tumor suppressors eliminates critical negative regulators of signaling. An examination of the PI3K-Akt and Ras-ERK pathways illustrates how such alterations dysregulate signaling in cancer and produce many of the characteristic features of tumor cells.
597 citations
TL;DR: The basic mechanisms and signaling pathways conserved between humans and flies responsible of inducing uncontrolled growth and cancer development are outlined and used to identify signals driving growth cell autonomously and within organs, drug discovery and for therapeutic approaches.
Abstract: Cancer is a multistep disease driven by the activation of specific oncogenic pathways concomitantly with the loss of function of tumor suppressor genes that act as sentinels to control physiological growth. The conservation of most of these signaling pathways in Drosophila, and the ability to easily manipulate them genetically, has made the fruit fly a useful model organism to study cancer biology. In this review we outline the basic mechanisms and signaling pathways conserved between humans and flies responsible of inducing uncontrolled growth and cancer development. Second, we describe classic and novel Drosophila models used to study different cancers, with the objective to discuss their strengths and limitations on their use to identify signals driving growth cell autonomously and within organs, drug discovery and for therapeutic approaches.
147 citations
Cites background from "Signaling Pathways that Control Cel..."
...Tumor cells escape the anti-proliferative effect of tumor suppressor genes, such as RB (retinoblastoma-associated) and TP53 genes (Duronio and Xiong, 2013), through mutations in these genes, which result in uncontrolled growth (Hanahan and Weinberg, 2000, 2011; Hariharan and Bilder, 2006)....
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TL;DR: Co-treatment with other chemotherapy drugs such as bortezomib, LY2940002, U0126, sunitinib, epirubicin, doxorubic in, temozolomide, and metformin enhances the anticancer potential of both formononetin and the respective drugs through synergistic effect.
Abstract: Cancer, a complex yet common disease, is caused by uncontrolled cell division and abnormal cell growth due to a variety of gene mutations. Seeking effective treatments for cancer is a major research focus, as the incidence of cancer is on the rise and drug resistance to existing anti-cancer drugs is major concern. Natural products have the potential to yield unique molecules and combinations of substances that may be effective against cancer with relatively low toxicity/better side effect profile compared to standard anticancer therapy. Drug discovery work with natural products has demonstrated that natural compounds display a wide range of biological activities correlating to anticancer effects. In this review, we discuss formononetin (C16H12O4), which originates mainly from red clovers and the Chinese herb Astragalus membranaceus. The compound comes from a class of 7-hydroisoflavones with a substitution of methoxy group at position 4. Formononetin elicits antitumorigenic properties in vitro and in vivo by modulating numerous signaling pathways to induce cell apoptosis (by intrinsic pathway involving Bax, Bcl-2, and caspase-3 proteins) and cell cycle arrest (by regulating mediators like cyclin A, cyclin B1, and cyclin D1), suppress cell proliferation [by signal transducer and activator of transcription (STAT) activation, phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT), and mitogen-activated protein kinase (MAPK) signaling pathway], and inhibit cell invasion [by regulating growth factors vascular endothelial growth factor (VEGF) and Fibroblast growth factor 2 (FGF2), and matrix metalloproteinase (MMP)-2 and MMP-9 proteins]. Co-treatment with other chemotherapy drugs such as bortezomib, LY2940002, U0126, sunitinib, epirubicin, doxorubicin, temozolomide, and metformin enhances the anticancer potential of both formononetin and the respective drugs through synergistic effect. Compiling the evidence thus far highlights the potential of formononetin to be a promising candidate for chemoprevention and chemotherapy.
139 citations
TL;DR: Recent advances in elucidating Cdt1 molecular functions in both origin licensing and kinetochore–microtubule attachment are reviewed, and the current understanding of human Cdt 1 regulation is described.
Abstract: Successful cell proliferation requires efficient and precise genome duplication followed by accurate chromosome segregation. The Cdc10-dependent transcript 1 protein (Cdt1) is required for the first step in DNA replication, and in human cells Cdt1 is also required during mitosis. Tight cell cycle controls over Cdt1 abundance and activity are critical to normal development and genome stability. We review here recent advances in elucidating Cdt1 molecular functions in both origin licensing and kinetochore-microtubule attachment, and we describe the current understanding of human Cdt1 regulation.
97 citations
Cites background from "Signaling Pathways that Control Cel..."
...The analogous function in metazoans is the responsibility of the E2F family of transcription factors, though the protein sequences of Cdc10 and E2F themselves are unrelated [115,116]....
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TL;DR: Six gene expression hallmarks of cellular ageing are identified, which encompass widely reported features of ageing such as increased senescence and inflammation, reduced electron transport chain activity and reduced ribosome synthesis, but also reveal a surprising lack of gene expression responses to known age-linked cellular stresses.
Abstract: Ageing leads to dramatic changes in the physiology of many different tissues resulting in a spectrum of pathology. Nonetheless, many lines of evidence suggest that ageing is driven by highly conserved cell intrinsic processes, and a set of unifying hallmarks of ageing has been defined. Here, we survey reports of age-linked changes in basal gene expression across eukaryotes from yeast to human and identify six gene expression hallmarks of cellular ageing: downregulation of genes encoding mitochondrial proteins; downregulation of the protein synthesis machinery; dysregulation of immune system genes; reduced growth factor signalling; constitutive responses to stress and DNA damage; dysregulation of gene expression and mRNA processing. These encompass widely reported features of ageing such as increased senescence and inflammation, reduced electron transport chain activity and reduced ribosome synthesis, but also reveal a surprising lack of gene expression responses to known age-linked cellular stresses. We discuss how the existence of conserved transcriptomic hallmarks relates to genome-wide epigenetic differences underlying ageing clocks, and how the changing transcriptome results in proteomic alterations where data is available and to variations in cell physiology characteristic of ageing. Identification of gene expression events that occur during ageing across distant organisms should be informative as to conserved underlying mechanisms of ageing, and provide additional biomarkers to assess the effects of diet and other environmental factors on the rate of ageing.
96 citations
Cites background from "Signaling Pathways that Control Cel..."
...Reduction in growth factor signalling Tight regulation of cell growth and division is essential for the development and survival of organisms and these processes are subject to the control of a vast network of intra- and extra-cellular signals (reviewed in Duronio and Xiong 2013)....
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References
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TL;DR: A gene is identified, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line and that could be an important mediator of p53-dependent tumor growth suppression.
8,339 citations
"Signaling Pathways that Control Cel..." refers background in this paper
...p53-mediated transcriptional activation of p21 following DNA damage was the first identified example of G1-phase regulation of a CKI gene (El-Deiry et al. 1993; Xiong et al. 1993b)....
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...…in stress responses, and defects in p53-mediated stress responses are associated with most types of human cancer. p53-mediated transcriptional activation of p21 following DNA damage was the first identified example of G1-phase regulation of a CKI gene (El-Deiry et al. 1993; Xiong et al. 1993b)....
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TL;DR: In this article, an improved two-hybrid system was employed to isolate human genes encoding Cdk-interacting proteins (Cips) and found that CIP1 is a potent, tight-binding inhibitor of Cdks and can inhibit the phosphorylation of Rb by cyclin A-Cdk2.
5,726 citations
"Signaling Pathways that Control Cel..." refers background in this paper
...…CKI characterized was mammalian p21 (also known as CDKN1A, CIP1, or WAF1), which binds to and Signaling to the G1 Cell Cycle Cite this article as Cold Spring Harb Perspect Biol 2013;5:a008904 5 inhibits the activity of multiple CDK–cyclin complexes (Xiong et al. 1992, 1993a; Harper et al. 1993)....
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TL;DR: Genetic alterations affecting p16INK4a and cyclin D1, proteins that govern phosphorylation of the retinoblastoma protein and control exit from the G1 phase of the cell cycle, are so frequent in human cancers that inactivation of this pathway may well be necessary for tumor development.
Abstract: Uncontrolled cell proliferation is the hallmark of cancer, and tumor cells have typically acquired damage to genes that directly regulate their cell cycles. Genetic alterations affecting p16(INK4a) and cyclin D1, proteins that govern phosphorylation of the retinoblastoma protein (RB) and control exit from the G1 phase of the cell cycle, are so frequent in human cancers that inactivation of this pathway may well be necessary for tumor development. Like the tumor suppressor protein p53, components of this "RB pathway," although not essential for the cell cycle per se, may participate in checkpoint functions that regulate homeostatic tissue renewal throughout life.
5,509 citations
TL;DR: The main role of pRB is to act as a signal transducer connecting the cell cycle clock with the transcriptional machinery, allowing the clock to control the expression of banks of genes that mediate advance of the cell through a critical phase of its growth cycle.
4,904 citations
TL;DR: P16 seems to act in a regulatory feedback circuit with CDK4, D-type cyclins and retinoblastoma protein, and inhibits the catalytic activity of theCDK4/cyclin D enzymes.
Abstract: The division cycle of eukaryotic cells is regulated by a family of protein kinases known as the cyclin-dependent kinases (CDKs). The sequential activation of individual members of this family and their consequent phosphorylation of critical substrates promotes orderly progression through the cell cycle. The complexes formed by CDK4 and the D-type cyclins have been strongly implicated in the control of cell proliferation during the G1 phase. CDK4 exists, in part, as a multi-protein complex with a D-type cyclin, proliferating cell nuclear antigen and a protein, p21 (refs 7-9). CDK4 associates separately with a protein of M(r) 16K, particularly in cells lacking a functional retinoblastoma protein. Here we report the isolation of a human p16 complementary DNA and demonstrate that p16 binds to CDK4 and inhibits the catalytic activity of the CDK4/cyclin D enzymes. p16 seems to act in a regulatory feedback circuit with CDK4, D-type cyclins and retinoblastoma protein.
3,716 citations
"Signaling Pathways that Control Cel..." refers background in this paper
...tinct CKI, p16 (also known as INK4A), was isolated around the same time and is a specific inhibitor of CDK4 (Serrano et al. 1993)....
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...A distinct CKI, p16 (also known as INK4A), was isolated around the same time and is a specific inhibitor of CDK4 (Serrano et al. 1993). p16 is the founding member of a separate family of INK4 CKIs that includes three additional proteins: p15 (also known as INK4B), p18 (also known as INK4C), and p19…...
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