p21: A Two-Faced Genome Guardian
TL;DR: The controversial aspects of the two-faced involvement of p21 in cancer are discussed and how this new information may increase the understanding of its role in cancer pathogenesis is speculated on.
About: This article is published in Trends in Molecular Medicine.The article was published on 2017-04-01. It has received 348 citations till now. The article focuses on the topics: Antiapoptotic Agent & Genome instability.
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TL;DR: In this article, the molecular mechanisms that underlie cellular senescence and the senescent associated growth arrest with a particular focus on why cells stop dividing, the stability of the growth arrest, the hypersecretory phenotype and how the different pathways are all integrated.
Abstract: Cellular senescence is a stable cell cycle arrest that can be triggered in normal cells in response to various intrinsic and extrinsic stimuli, as well as developmental signals Senescence is considered to be a highly dynamic, multi-step process, during which the properties of senescent cells continuously evolve and diversify in a context dependent manner It is associated with multiple cellular and molecular changes and distinct phenotypic alterations, including a stable proliferation arrest unresponsive to mitogenic stimuli Senescent cells remain viable, have alterations in metabolic activity and undergo dramatic changes in gene expression and develop a complex senescence-associated secretory phenotype Cellular senescence can compromise tissue repair and regeneration, thereby contributing toward aging Removal of senescent cells can attenuate age-related tissue dysfunction and extend health span Senescence can also act as a potent anti-tumor mechanism, by preventing proliferation of potentially cancerous cells It is a cellular program which acts as a double-edged sword, with both beneficial and detrimental effects on the health of the organism, and considered to be an example of evolutionary antagonistic pleiotropy Activation of the p53/p21WAF1/CIP1 and p16INK4A/pRB tumor suppressor pathways play a central role in regulating senescence Several other pathways have recently been implicated in mediating senescence and the senescent phenotype Herein we review the molecular mechanisms that underlie cellular senescence and the senescence associated growth arrest with a particular focus on why cells stop dividing, the stability of the growth arrest, the hypersecretory phenotype and how the different pathways are all integrated
391 citations
TL;DR: This review will focus on targeting p21 in cancer research and its potential in providing novel therapies as well as therapeutic approaches in cancer field.
Abstract: p21 functions as a cell cycle inhibitor and anti-proliferative effector in normal cells, and is dysregulated in some cancers. Earlier observations on p21 knockout models emphasized the role of this protein in cell cycle arrest under the p53 transcription factor activity. Although tumor-suppressor function of p21 is the most studied aspect of this protein in cancer, the role of p21 in phenotypic plasticity and its oncogenic/anti-apoptotic function, depending on p21 subcellular localization and p53 status, have been under scrutiny recently. Basic science and translational studies use precision gene editing to manipulate p21 itself, and proteins that interact with it; these studies have led to regulatory/functional/drug sensitivity discoveries as well as therapeutic approaches in cancer field. In this review, we will focus on targeting p21 in cancer research and its potential in providing novel therapies.
172 citations
Cites background from "p21: A Two-Faced Genome Guardian"
...Controversial aspects of p21 is decided by p21 location and p53 protein condition [16]....
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...The dual role of p21 in cancer progression as an oncogene and tumor suppressor [16,148] makes it harder to have one approach for all cancer types; nevertheless, according to the literature, we believe that p21 induction has a synergic effect on other treatments, as it has been shown for several combination therapies, mentioned in this review [149]....
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...has argued that rare p21 mutation rate in cancer might be due to an evolutionary favorable tumor heterogenicity, enforced by p53-independent p21 activity [16]....
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TL;DR: It is proposed that these shared transcriptome profiles will enable the identification of senescent cells in vivo, the investigation of their roles in aging and malignancy and the development of strategies to target senescence cells therapeutically.
Abstract: Cellular senescence, an integral component of aging and cancer, arises in response to diverse triggers, including telomere attrition, macromolecular damage and signaling from activated oncogenes. At present, senescent cells are identified by the combined presence of multiple traits, such as senescence-associated protein expression and secretion, DNA damage and β-galactosidase activity; unfortunately, these traits are neither exclusively nor universally present in senescent cells. To identify robust shared markers of senescence, we have performed RNA-sequencing analysis across eight diverse models of senescence triggered in human diploid fibroblasts (WI-38, IMR-90) and endothelial cells (HUVEC, HAEC) by replicative exhaustion, exposure to ionizing radiation or doxorubicin, and expression of the oncogene HRASG12V. The intersection of the altered transcriptomes revealed 50 RNAs consistently elevated and 18 RNAs consistently reduced across all senescence models, including many protein-coding mRNAs and some non-coding RNAs. We propose that these shared transcriptome profiles will enable the identification of senescent cells in vivo, the investigation of their roles in aging and malignancy and the development of strategies to target senescent cells therapeutically.
164 citations
TL;DR: The protein p21 is the founding member of cyclin-dependent kinase inhibitors and an important versatile cell cycle protein that acts either as a tumor suppressor or as an oncogene depending largely on the cellular context, its subcellular localization and posttranslational modifications.
Abstract: Loss of cell cycle control is characteristic of tumorigenesis. The protein p21 is the founding member of cyclin-dependent kinase inhibitors and an important versatile cell cycle protein. p21 is transcriptionally controlled by p53 and p53-independent pathways. Its expression is increased in response to various intra- and extracellular stimuli to arrest the cell cycle ensuring genomic stability. Apart from its roles in cell cycle regulation including mitosis, p21 is involved in differentiation, cell migration, cytoskeletal dynamics, apoptosis, transcription, DNA repair, reprogramming of induced pluripotent stem cells, autophagy and the onset of senescence. p21 acts either as a tumor suppressor or as an oncogene depending largely on the cellular context, its subcellular localization and posttranslational modifications. In the present review, we briefly mention the general functions of p21 and summarize its roles in differentiation, migration and invasion in detail. Finally, regarding its dual role as tumor suppressor and oncogene, we highlight the potential, difficulties and risks of using p21 as a biomarker as well as a therapeutic target.
157 citations
TL;DR: In this paper , the p53-p21-RB signaling pathway is examined and the mechanism of regulation by p53p21 -RB signaling is assessed and the overlap with p53 p21-DREAM signaling is examined.
Abstract: The retinoblastoma protein RB and the transcription factor p53 are central tumor suppressors. They are often found inactivated in various tumor types. Both proteins play central roles in regulating the cell division cycle. RB forms complexes with the E2F family of transcription factors and downregulates numerous genes. Among the RB-E2F target genes, a large number code for key cell cycle regulators. Their transcriptional repression by the RB-E2F complex is released through phosphorylation of RB, leading to expression of the cell cycle regulators. The release from repression can be prevented by the cyclin-dependent kinase inhibitor p21/CDKN1A. The CDKN1A gene is transcriptionally activated by p53. Taken together, these elements constitute the p53-p21-RB signaling pathway. Following activation of p53, for example by viral infection or induction of DNA damage, p21 expression is upregulated. High levels of p21 then result in RB-E2F complex formation and downregulation of a large number of cell cycle genes. Thus, p53-dependent transcriptional repression is indirect. The reduced expression of the many regulators leads to cell cycle arrest. Examination of the p53-p21-RB targets and genes controlled by the related p53-p21-DREAM signaling pathway reveals that there is a large overlap of the two groups. Mechanistically this can be explained by replacing RB-E2F complexes with the DREAM transcriptional repressor complex at E2F sites in target promoters. In contrast to RB-E2F, DREAM can downregulate genes also through CHR transcription factor binding sites. This results in a distinct gene set controlled by p53-p21-DREAM signaling independent of RB-E2F. Furthermore, RB has non-canonical functions without binding to E2F and DNA. Such a role of RB supporting DREAM formation may be exerted by the RB-SKP2-p27-cyclin A/E-CDK2-p130-DREAM link. In the current synopsis, the mechanism of regulation by p53-p21-RB signaling is assessed and the overlap with p53-p21-DREAM signaling is examined.
132 citations
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TL;DR: It is found that over expression of p21 inhibits the activity of each member of the cyclin/CDK family, and this results indicate that p21 may be a universal inhibitor of cyclin kinases.
Abstract: Deregulation of cell proliferation is a hallmark of neoplastic transformation. Alteration in growth control pathways must translate into changes in the cell-cycle regulatory machinery, but the mechanism by which this occurs is largely unknown. Compared with normal human fibroblasts, cells transformed with a variety of viral oncoproteins show striking changes in the subunit composition of the cyclin-dependent kinases (CDKs). In normal cells, CDKs exist predominantly in multiple quaternary complexes, each containing a CDK, cyclin, proliferating cell nuclear antigen and the p21 protein. However, in many transformed cells, proliferating cell nuclear antigen and p21 are lost from these multiprotein enzymes. Here we have investigated the significance of this phenomenon by molecular cloning of p21 and in vitro reconstitution of the quaternary cell-cycle kinase complexes. We find that p21 inhibits the activity of each member of the cyclin/CDK family. Furthermore, overexpression of p21 inhibits the proliferation of mammalian cells. Our results indicate that p21 may be a universal inhibitor of cyclin kinases.
3,442 citations
TL;DR: This Review focuses on recent advances in the understanding of the regulation of p21 and its biological functions with emphasis on its p53-independent tumour suppressor activities and paradoxical tumour-promoting activities, and their implications in cancer.
Abstract: One of the main engines that drives cellular transformation is the loss of proper control of the mammalian cell cycle. The cyclin-dependent kinase inhibitor p21 (also known as p21WAF1/Cip1) promotes cell cycle arrest in response to many stimuli. It is well positioned to function as both a sensor and an effector of multiple anti-proliferative signals. This Review focuses on recent advances in our understanding of the regulation of p21 and its biological functions with emphasis on its p53-independent tumour suppressor activities and paradoxical tumour-promoting activities, and their implications in cancer.
2,247 citations
Journal Article•
TL;DR: The results support the idea that WAF1/CIP1 is a critical downstream effector in the p53-specific pathway of growth control in mammalian cells.
Abstract: The tumor growth suppressor WAF1/CIP1 was recently shown to be induced by p53 and to be a potent inhibitor of cyclin-dependent kinases In the present studies, we sought to determine the relationship between the expression of WAF1/CIP1 and endogenous regulation of p53 function WAF1/CIP1 protein was first localized to the nucleus of cells containing wild-type p53 and undergoing G 1 arrest WAF1/CIP1 was induced in wild-type p53-containing cells by exposure to DNA damaging agents, but not in mutant p53 -containing cells The induction of WAF1/CIP1 protein occurred in cells undergoing either p53 -associated G 1 arrest or apoptosis but not in cells induced to arrest in G 1 or to undergo apoptosis through p53 -independent mechanisms DNA damage led to increased levels of WAF1/CIP1 in cyclin E-containing complexes and to an associated decrease in cyclin-dependent kinase activity These results support the idea that WAF1/CIP1 is a critical downstream effector in the p53 -specific pathway of growth control in mammalian cells
2,056 citations
TL;DR: The mutation patterns of the tumour suppressor TP53, ataxia telangiectasia mutated (ATM) and cyclin-dependent kinase inhibitor 2A (CDKN2A; which encodes p16INK4A and p14ARF) support the oncogene-induced DNA replication stress model, which attributes genomic instability and TP53 and ATM mutations to oncogen- induced DNA damage.
Abstract: Genomic instability is a characteristic of most cancers. In hereditary cancers, genomic instability results from mutations in DNA repair genes and drives cancer development, as predicted by the mutator hypothesis. In sporadic (non-hereditary) cancers the molecular basis of genomic instability remains unclear, but recent high-throughput sequencing studies suggest that mutations in DNA repair genes are infrequent before therapy, arguing against the mutator hypothesis for these cancers. Instead, the mutation patterns of the tumour suppressor TP53 (which encodes p53), ataxia telangiectasia mutated (ATM) and cyclin-dependent kinase inhibitor 2A (CDKN2A; which encodes p16INK4A and p14ARF) support the oncogene-induced DNA replication stress model, which attributes genomic instability and TP53 and ATM mutations to oncogene-induced DNA damage.
1,935 citations
TL;DR: Oncogene-induced DNA damage may explain two key features of cancer: genomic instability and the high frequency of p53 mutations.
Abstract: Of all types of DNA damage, DNA double-strand breaks (DSBs) pose the greatest challenge to cells. One might have, therefore, anticipated that a sizable number of DNA DSBs would be incompatible with cell proliferation. Yet recent experimental findings suggest that, in both precancerous lesions and cancers, activated oncogenes induce stalling and collapse of DNA replication forks, which in turn leads to formation of DNA DSBs. This continuous formation of DNA DSBs may contribute to the genomic instability that characterizes the vast majority of human cancers. In addition, in precancerous lesions, these DNA DSBs activate p53, which, by inducing apoptosis or senescence, raises a barrier to tumor progression. Breach of this barrier by various mechanisms, most notably by p53 mutations, that impair the DNA damage response pathway allows cancers to develop. Thus, oncogene-induced DNA damage may explain two key features of cancer: genomic instability and the high frequency of p53 mutations.
1,714 citations