scholarly journals Pan-Cancer Molecular Patterns and Biological Implications Associated with a Tumor-Specific Molecular Signature

Cells ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 45
Author(s):  
Darío Rocha ◽  
Iris A. García ◽  
Aldana González Montoro ◽  
Andrea Llera ◽  
Laura Prato ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Uncertainty Assessment ◽  
Cell Cycle Checkpoints ◽  
Molecular Signature ◽  
Cancer Subtypes ◽  
United States Food ◽  
Cancer Types ◽  
Molecular Patterns ◽  
Pan Cancer

Studying tissue-independent components of cancer and defining pan-cancer subtypes could be addressed using tissue-specific molecular signatures if classification errors are controlled. Since PAM50 is a well-known, United States Food and Drug Administration (FDA)-approved and commercially available breast cancer signature, we applied it with uncertainty assessment to classify tumor samples from over 33 cancer types, discarded unassigned samples, and studied the emerging tumor-agnostic molecular patterns. The percentage of unassigned samples ranged between 55.5% and 86.9% in non-breast tissues, and gene set analysis suggested that the remaining samples could be grouped into two classes (named C1 and C2) regardless of the tissue. The C2 class was more dedifferentiated, more proliferative, with higher centrosome amplification, and potentially more TP53 and RB1 mutations. We identified 28 gene sets and 95 genes mainly associated with cell-cycle progression, cell-cycle checkpoints, and DNA damage that were consistently exacerbated in the C2 class. In some cancer types, the C1/C2 classification was associated with survival and drug sensitivity, and modulated the prognostic meaning of the immune infiltrate. Our results suggest that PAM50 could be repurposed for a pan-cancer context when paired with uncertainty assessment, resulting in two classes with molecular, biological, and clinical implications.

scholarly journals Characterization of the Survival Influential Genes in Carcinogenesis

2021 ◽  
Vol 22 (9) ◽  
pp. 4384
Author(s):  
Divya Sahu ◽  
Yu-Lin Chang ◽  
Yin-Chen Lin ◽  
Chen-Ching Lin
Keyword(s):  
Cell Cycle ◽  
Cox Regression ◽  
Monte Carlo Algorithm ◽  
Functional Modules ◽  
Protective Genes ◽  
Cancer Types ◽  
Underlying Mechanisms ◽  
Patient Prognosis ◽  
Pan Cancer

The genes influencing cancer patient mortality have been studied by survival analysis for many years. However, most studies utilized them only to support their findings associated with patient prognosis: their roles in carcinogenesis have not yet been revealed. Herein, we applied an in silico approach, integrating the Cox regression model with effect size estimated by the Monte Carlo algorithm, to screen survival-influential genes in more than 6000 tumor samples across 16 cancer types. We observed that the survival-influential genes had cancer-dependent properties. Moreover, the functional modules formed by the harmful genes were consistently associated with cell cycle in 12 out of the 16 cancer types and pan-cancer, showing that dysregulation of the cell cycle could harm patient prognosis in cancer. The functional modules formed by the protective genes are more diverse in cancers; the most prevalent functions are relevant for immune response, implying that patients with different cancer types might develop different mechanisms against carcinogenesis. We also identified a harmful set of 10 genes, with potential as prognostic biomarkers in pan-cancer. Briefly, our results demonstrated that the survival-influential genes could reveal underlying mechanisms in carcinogenesis and might provide clues for developing therapeutic targets for cancers.

Parkinson´s related protein DJ-1 is involved in aberrant cell cycle re-entry through Cdk5

2020 ◽  
Author(s):  
Mª José López-Grueso ◽  
Carmen Alicia Padilla ◽  
José Antonio Bárcena ◽  
Raquel Requejo-Aguilar
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Cortical Neurons ◽  
Cell Cycle Progression ◽  
Cell Cycle Checkpoints ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
Multifunctional Protein ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase

Abstract DJ-1 is a multifunctional protein involved in Parkinson disease (PD) that can act as antioxidant, molecular chaperone, protease, glyoxalase and transcriptional regulator. However, the exact mechanism by which DJ-1 dysfunction contributes to development of Parkinson´s disease remains elusive. Here, using a comparative proteomic analysis between normal cortical neurons and neurons lacking DJ-1, we show that this protein is involved in cell cycle checkpoints disruption as a consequence of increased amount of p-Tau and a-synuclein proteins, altered signalling pathways, as the phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK), and deregulation of cyclin-dependent kinase 5 (Cdk5). Cdk5 is normally involved in dendritic growth, axon formation and the establishment of synapses, but can also contribute to cell cycle progression, as in our case, in pathological conditions. In addition, we observed a decrease in proteasomal activity, probably due to Tau phosphorylation that can also lead to activation of mitogenic signalling pathways. Taken together, our findings indicate, for the first time, that aborted cell cycle re-entry could be at the onset of DJ-1 associated PD. Thereby, new approaches targeting cell cycle re-entry can be envisaged to improve current therapeutic strategies.

scholarly journals Efficient weighted univariate clustering maps outstanding dysregulated genomic zones in human cancers

2020 ◽  
Vol 36 (20) ◽  
pp. 5027-5036 ◽  
Author(s):  
Mingzhou Song ◽  
Hua Zhong
Keyword(s):  
Clustering Algorithm ◽  
Human Cancer ◽  
Clustering Algorithms ◽  
Search Space ◽  
R Package ◽  
Supplementary Information ◽  
Diagnostic Biomarkers ◽  
Cancer Types ◽  
Molecular Patterns ◽  
Pan Cancer

Abstract Motivation Chromosomal patterning of gene expression in cancer can arise from aneuploidy, genome disorganization or abnormal DNA methylation. To map such patterns, we introduce a weighted univariate clustering algorithm to guarantee linear runtime, optimality and reproducibility. Results We present the chromosome clustering method, establish its optimality and runtime and evaluate its performance. It uses dynamic programming enhanced with an algorithm to reduce search-space in-place to decrease runtime overhead. Using the method, we delineated outstanding genomic zones in 17 human cancer types. We identified strong continuity in dysregulation polarity—dominance by either up- or downregulated genes in a zone—along chromosomes in all cancer types. Significantly polarized dysregulation zones specific to cancer types are found, offering potential diagnostic biomarkers. Unreported previously, a total of 109 loci with conserved dysregulation polarity across cancer types give insights into pan-cancer mechanisms. Efficient chromosomal clustering opens a window to characterize molecular patterns in cancer genome and beyond. Availability and implementation Weighted univariate clustering algorithms are implemented within the R package ‘Ckmeans.1d.dp’ (4.0.0 or above), freely available at https://cran.r-project.org/package=Ckmeans.1d.dp. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Evidence that the cell cycle is a series of uncoupled, memoryless phases

2018 ◽  
Author(s):  
Hui Xiao Chao ◽  
Randy I. Fakhreddin ◽  
Hristo K. Shimerov ◽  
Rashmi J. Kumar ◽  
Gaorav P. Gupta ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Synthesis ◽  
Cell Cycle Progression ◽  
Phase 1 ◽  
Cell Cycle Phase ◽  
Cell Cycle Checkpoints ◽  
Cycle Phase ◽  
Erlang Distribution ◽  
Cycle Progression ◽  
Gap Phase

The cell cycle is canonically described as a series of 4 phases: G1 (gap phase 1), S (DNA synthesis), G2 (gap phase 2), and M (mitosis). Various models have been proposed to describe the durations of each phase, including a two-state model with fixed S-G2-M duration and random G1 duration1,2; a “stretched” model in which phase durations are proportional3; and an inheritance model in which sister cells show correlated phase durations2,4. A fundamental challenge is to understand the quantitative laws that govern cell-cycle progression and to reconcile the evidence supporting these different models. Here, we used time-lapse fluorescence microscopy to quantify the durations of G1, S, G2, and M phases for thousands of individual cells from three human cell lines. We found no evidence of correlation between any pair of phase durations. Instead, each phase followed an Erlang distribution with a characteristic rate and number of steps. These observations suggest that each cell cycle phase is memoryless with respect to previous phase durations. We challenged this model by perturbing the durations of specific phases through oncogene activation, inhibition of DNA synthesis, reduced temperature, and DNA damage. Phase durations remained uncoupled in individual cells despite large changes in durations in cell populations. To explain this behavior, we propose a mathematical model in which the independence of cell-cycle phase durations arises from a large number of molecular factors that each exerts a minor influence on the rate of cell-cycle progression. The model predicts that it is possible to force correlations between phases by making large perturbations to a single factor that contributes to more than one phase duration, which we confirmed experimentally by inhibiting cyclin-dependent kinase 2 (CDK2). We further report that phases can show coupling under certain dysfunctional states such as in a transformed cell line with defective cell cycle checkpoints. This quantitative model of cell cycle progression explains the paradoxical observation that phase durations are both inherited and independent and suggests how cell cycle progression may be altered in disease states.

scholarly journals The Atypical Cyclin-Like Protein Spy1 Overrides p53-Mediated Tumour Suppression and Promotes Susceptibility to Breast Tumorigenesis

2019 ◽  
Author(s):  
Bre-Anne Fifield ◽  
Ingrid Qemo ◽  
Evie Kirou ◽  
Robert D. Cardiff ◽  
Lisa Ann Porter
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Lobular Carcinoma ◽  
Critical Role ◽  
Mammary Epithelium ◽  
Cell Cycle Checkpoints ◽  
Checkpoint Control ◽  
Breast Tumorigenesis ◽  
Protein Activity ◽  
Protein Levels

AbstractBreast cancer is the most common cancer to affect women and one of the leading causes of cancer related deaths. Maintenance of genomic stability and proper regulation of cell cycle checkpoints play a critical role in preventing the accumulation of deleterious mutations. Perturbations in the expression or activity of mediators of cell cycle progression or checkpoint activation represent important events that may increase susceptibility to the onset of carcinogenesis. The atypical cyclin-like protein Spy1 was isolated in a screen for novel genes that could bypass the DNA damage response. Clinical data demonstrates that protein levels of Spy1 are significantly elevated in ductal and lobular carcinoma of the breast. Using a transgenic mouse driving expression of Spy1 in the mammary epithelium we demonstrate that sustained elevation of Spy1 leads to enhanced proliferation and an increased susceptibility to mammary tumour formation. We find that Spy1 is targeted for degradation by the tumour suppressor p53 to protect checkpoint control. When crossed with p53 deficient mice, elevation of Spy1 leads to an increase in hyperplastic alveolar nodules. Targeting cyclin-like protein activity may therefore represent a mechanism of re-sensitizing cells to important cell cycle checkpoints in a therapeutic setting.

scholarly journals TIF1 Proteins in Genome Stability and Cancer

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2094 ◽  
Author(s):  
Roisin M. McAvera ◽  
Lisa J. Crawford
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Genome Stability ◽  
Cell Cycle Progression ◽  
Binding Proteins ◽  
Chromatin Binding ◽  
Cycle Progression ◽  
E3 Ligases ◽  
Cancer Types ◽  
Cycle Regulation

Genomic instability is a hallmark of cancer cells which results in excessive DNA damage. To counteract this, cells have evolved a tightly regulated DNA damage response (DDR) to rapidly sense DNA damage and promote its repair whilst halting cell cycle progression. The DDR functions predominantly within the context of chromatin and requires the action of chromatin-binding proteins to coordinate the appropriate response. TRIM24, TRIM28, TRIM33 and TRIM66 make up the transcriptional intermediary factor 1 (TIF1) family of chromatin-binding proteins, a subfamily of the large tripartite motif (TRIM) family of E3 ligases. All four TIF1 proteins are aberrantly expressed across numerous cancer types, and increasing evidence suggests that TIF1 family members can function to maintain genome stability by mediating chromatin-based responses to DNA damage. This review provides an overview of the TIF1 family in cancer, focusing on their roles in DNA repair, chromatin regulation and cell cycle regulation.

scholarly journals The DNA Damage-Induced Cell Cycle Checkpoints

2000 ◽  
Vol 2 (4) ◽  
pp. 237-243
Author(s):  
Piotr Widlak
Keyword(s):  
Cell Cycle ◽  
Signal Transduction ◽  
Dna Damage ◽  
Tumor Suppressor ◽  
Cell Cycle Progression ◽  
P53 Protein ◽  
Critical Role ◽  
Cell Cycle Checkpoints ◽  
Signal Transduction Pathways ◽  
Cycle Progression

The proliferation of eukaryotic cells is driven by a process called the cell cycle. Proper regulation of this process, leading to orderly execution of sequential steps within the cycle, ensures normal development and homeostasis of the organism. On the other hand, perturbations of the cell cycle are frequently attributed to cancer cells. Mechanisms that ensure the order and fidelity of events in the cell cycle are called checkpoints. The checkpoints induced by damaged DNA delay the cell cycle progression, providing more time for repair of lesion before DNA replication and segregation. The DNA damage-induced checkpoints can be recognized as signal transduction pathways that communicate information between DNA lesion and components of the cell cycle. Proteins involved in the cell cycle, as well as components of the signal transduction pathways communicating with the cell cycle, are frequently products of oncogenes and tumor suppressor genes. Malfunction of these genes plays a critical role in the development of human cancers. The key component in the checkpoint machinery is tumor suppressor gene p53, involved in either regulation of the cell cycle progression (e.g. Gl arrest of cells treated with DNA damaging factor) or activation of programmed cell death (apoptosis). It is postulated that p53 protein is activated by DNA damage detectors. One of the candidates for this role is DNA-dependent protein kinase (DNA-PK) which recognizes DNA strand breaks and phosphorylates p53 protein.

scholarly journals Dominant role of CDKN2B/p15INK4B of 9p21.3 tumor suppressor hub in inhibition of cell-cycle and glycolysis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yong Xia ◽  
Yan Liu ◽  
Chao Yang ◽  
Diane M. Simeone ◽  
Tung-Tien Sun ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Dominant Role ◽  
Glycolytic Enzyme ◽  
Cycle Progression ◽  
Cancer Types ◽  
Artery Disease

AbstractHuman chromosome 9p21.3 is susceptible to inactivation in cell immortalization and diseases, such as cancer, coronary artery disease and type-2 diabetes. Although this locus encodes three cyclin-dependent kinase (CDK) inhibitors (p15INK4B, p14ARF and p16INK4A), our understanding of their functions and modes of action is limited to the latter two. Here, we show that in vitro p15INK4B is markedly stronger than p16INK4A in inhibiting pRb1 phosphorylation, E2F activity and cell-cycle progression. In mice, urothelial cells expressing oncogenic HRas and lacking p15INK4B, but not those expressing HRas and lacking p16INK4A, develop early-onset bladder tumors. The potency of CDKN2B/p15INK4B in tumor suppression relies on its strong binding via key N-terminal residues to and inhibition of CDK4/CDK6. p15INK4B also binds and inhibits enolase-1, a glycolytic enzyme upregulated in most cancer types. Our results highlight the dual inhibition of p15INK4B on cell proliferation, and unveil mechanisms whereby p15INK4B aberrations may underpin cancer and non-cancer conditions.

scholarly journals Checkpoint non-fidelity induces a complex landscape of lineage fitness after DNA damage

2018 ◽  
Author(s):  
Callum J. Campbell ◽  
Ashok R. Venkitaraman ◽  
Alessandro Esposito
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Fate ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Dna Lesions ◽  
Lineage Tracing ◽  
Cell Cycle Checkpoints ◽  
Complex Landscape ◽  
Cellular Dna

AbstractDNA damage in proliferating mammalian cells causes death1, senescence2 or continued survival, via checkpoints that monitor damage and regulate cell cycle progression, DNA repair and fate determination3. Cell cycle checkpoints facilitate tumour suppression by preventing the generation of proliferating mutated cells4, particularly by blocking passage of DNA lesions into replication and mitosis5. While checkpoint non-fidelity permits cells to carry genomic aberrations into subsequent cell cycle phases6, its long-term consequences on lineages descendant from damaged cells remains poorly characterised. Devising methods for microscopy-based lineage tracing, we unexpectedly demonstrate that transient DNA damage to single living cells bearing a negligent checkpoint induces heterogenous cell-fate outcomes in their descendant generations removed from the initial insult. After transiently damaged cells undergo an initial arrest, pairs of descendant cells without obvious cell-cycle abnormalities either divide or die in a seemingly stochastic way. Progeny of transiently damaged cells may die generations afterwards, creating considerable variability of lineage fitness that promotes overall persistence in a mutagenic environment. Descendants of damaged cells frequently form micronuclei, activating immunogenic signalling. Our findings reveal previously unrecognized, heterogenous effects of cellular DNA damage that manifest long afterwards in descendant cells. We suggest that these heterogenous descendant cell-fate responses may function physiologically to ensure the elimination and immune clearance of damaged cell lineages, but pathologically, may enable the prolonged survival of cells bearing mutagenic damage.

Natural sourced inhibitors of EGFR, PDGFR, FGFR and VEGFR-mediated signaling pathways as potential anticancer agents

2021 ◽  
Vol 28 ◽  
Author(s):  
Sisir Nandi ◽  
Rishita Dey ◽  
Asmita Samadder ◽  
Aaruni Saxena ◽  
Anil Kumar Saxena
Keyword(s):  
Cell Cycle ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Mitotic Cell ◽  
Cell Cycle Checkpoints ◽  
Signalling Pathways ◽  
Mitotic Cell Cycle ◽  
Cycle Progression

: The molecular mechanisms of mitotic cell cycle progression involve very tightly restricted types of machinery which are highly regulated by a fine balance between the positive and negative accelerators (or regulators). These regulators include several checkpoints that have proteins acting as enzymes and their activating partners. These checkpoints incessantly monitor the external as well as internal environments such as growth signals, favorable conditions for growth, cell size, DNA integrity of the cell and hence function to maintain the highly ordered cell cycle progression by sustaining cell homeostasis and promotes error-free DNA replication and cell cycle, division. To progress through the mitotic cell cycle, the cell has to successfully drive past the cell cycle checkpoints. Due to the abnormal behavior of some cell cycle proteins, the cells tend to divide continuously overcoming the tight regulation of cell cycle checkpoints. Such anomalies may lead to unwanted cell division and this deregulation of cell cycle events is considered as one of the main reasons behind tumor development and thus cancer progression. So the understanding of the molecular mechanisms in cancer progression might be insightful for designing several cancer treatment strategies. The deregulation in the checkpoints is caused due to the changes brought in the tyrosine residues of TPKs via PDGFR, EGFR, FGFR, and VEGFR-mediated signalling pathways. Therefore, the inhibitors of PDGFR, EGFR, FGFR, and VEGFR-mediated signalling pathways would be potential anticancer agents. The resistance and toxicity in the existing synthetic anticancer chemotherapeutics may decrease the life span of a patient. For a long, natural products have always played an essential alternative source of therapeutic agents due to having the least or no side effect and toxicity. The present study is an attempt to promote the natural anticancer drug development focusing on the updated structural information of PDGFR, EGFR, FGFR, and VEGFR inhibitors isolated from the plant sources. The data used in this review has been collected from internet resources viz. GOOGLE Web, GOOGLE SCHOLAR, and PubMed Central. The citation of each report was first checked after which the articles were selected as an authentic reference for the present study. Around 200 journal articles were selected of which around 142 were selected finally for presenting the study on the natural sourced inhibitors of EGFR, PDGFR, FGFR, and VEGFR-mediated signaling pathways which would help in the potential cancer treatment.

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