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Computational analysis of dynamical responses to the intrinsic pathway of programmed cell death.

ABSTRACT: Multicellular organisms shape development and remove aberrant cells by programmed cell death ("apoptosis"). Because defective cell death (too little or too much) is implicated in various diseases (like cancer and autoimmunity), understanding how apoptosis is regulated is an important goal of molecular cell biologists. To this end, we propose a mathematical model of the intrinsic apoptotic pathway that captures three key dynamical features: a signal threshold to elicit cell death, irreversible commitment to the response, and a time delay that is inversely proportional to signal strength. Subdividing the intrinsic pathway into three modules (initiator, amplifier, executioner), we use computer simulation and bifurcation theory to attribute signal threshold and time delay to positive feedback in the initiator module and irreversible commitment to positive feedback in the executioner module. The model accounts for the behavior of mutants deficient in various genes and is used to design experiments that would test its basic assumptions. Finally, we apply the model to study p53-induced cellular responses to DNA damage. Cells first undergo cell cycle arrest and DNA repair, and then apoptosis if the damage is beyond repair. The model ascribes this cell-fate transition to a transformation of p53 from "helper" to "killer" forms.

SUBMITTER: Zhang T

PROVIDER: S-EPMC2711321 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Computational analysis of dynamical responses to the intrinsic pathway of programmed cell death.

Zhang Tongli T Brazhnik Paul P Tyson John J JJ

Biophysical journal 20090701 2

Multicellular organisms shape development and remove aberrant cells by programmed cell death ("apoptosis"). Because defective cell death (too little or too much) is implicated in various diseases (like cancer and autoimmunity), understanding how apoptosis is regulated is an important goal of molecular cell biologists. To this end, we propose a mathematical model of the intrinsic apoptotic pathway that captures three key dynamical features: a signal threshold to elicit cell death, irreversible co ...[more]

PMID: 19619456

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Project description:It is recognized now that intrinsically disordered proteins (IDPs), which do not have unique 3D structures as a whole or in noticeable parts, constitute a significant fraction of any given proteome. IDPs are characterized by an astonishing structural and functional diversity that defines their ability to be universal regulators of various cellular pathways. Programmed cell death (PCD) is one of the most intricate cellular processes where the cell uses specialized cellular machinery and intracellular programs to kill itself. This cell-suicide mechanism enables metazoans to control cell numbers and to eliminate cells that threaten the animal's survival. PCD includes several specific modules, such as apoptosis, autophagy, and programmed necrosis (necroptosis). These modules are not only tightly regulated but also intimately interconnected and are jointly controlled via a complex set of protein-protein interactions. To understand the role of the intrinsic disorder in controlling and regulating the PCD, several large sets of PCD-related proteins across 28 species were analyzed using a wide array of modern bioinformatics tools. This study indicates that the intrinsic disorder phenomenon has to be taken into consideration to generate a complete picture of the interconnected processes, pathways, and modules that determine the essence of the PCD. We demonstrate that proteins involved in regulation and execution of PCD possess substantial amount of intrinsic disorder. We annotate functional roles of disorder across and within apoptosis, autophagy, and necroptosis processes. Disordered regions are shown to be implemented in a number of crucial functions, such as protein-protein interactions, interactions with other partners including nucleic acids and other ligands, are enriched in post-translational modification sites, and are characterized by specific evolutionary patterns. We mapped the disorder into an integrated network of PCD pathways and into the interactomes of selected proteins that are involved in the p53-mediated apoptotic signaling pathway.

Project description:A major pathophysiologic mechanism in sepsis is impaired host immunity which results in failure to eradicate invading pathogens and increased susceptibility to secondary infections. Although many immunosuppressive mechanisms exist, increased expression of the inhibitory receptor programmed cell death 1 (PD-1) and its ligand (PD-L1) are thought to play key roles. The newly recognized phenomenon of T cell exhaustion is mediated in part by PD-1 effects on T cells. This study tested the ability of anti-PD-1 and anti-PD-L1 antibodies to prevent apoptosis and improve lymphocyte function in septic patients.Blood was obtained from 43 septic and 15 non-septic critically-ill patients. Effects of anti-PD-1, anti-PD-L1, or isotype-control antibody on lymphocyte apoptosis and interferon gamma (IFN-?) and interleukin-2 (IL-2) production were quantitated by flow cytometry.Lymphocytes from septic patients produced decreased IFN-? and IL-2 and had increased CD8 T cell expression of PD-1 and decreased PD-L1 expression compared to non-septic patients (P<0.05). Monocytes from septic patients had increased PD-L1 and decreased HLA-DR expression compared to non-septic patients (P<0.01). CD8 T cell expression of PD-1 increased over time in ICU as PD-L1, IFN-?, and IL2 decreased. In addition, donors with the highest CD8 PD-1 expression together with the lowest CD8 PD-L1 expression also had lower levels of HLA-DR expression in monocytes, and an increased rate of secondary infections, suggestive of a more immune exhausted phenotype. Treatment of cells from septic patients with anti-PD-1 or anti-PD-L1 antibody decreased apoptosis and increased IFN-? and IL-2 production in septic patients; (P<0.01). The percentage of CD4 T cells that were PD-1 positive correlated with the degree of cellular apoptosis (P<0.01).In vitro blockade of the PD-1:PD-L1 pathway decreases apoptosis and improves immune cell function in septic patients. The current results together with multiple positive studies of anti-PD-1 and anti-PD-L1 in animal models of bacterial and fungal infections and the relative safety profile of anti-PD-1/anti-PD-L1 in human oncology trials to date strongly support the initiation of clinical trials testing these antibodies in sepsis, a disorder with a high mortality.

Project description:Diatoms are important phytoplankton and contribute greatly to the primary productivity of marine ecosystems. Despite the ecological significance of diatoms and the importance of programmed cell death (PCD) in the fluctuation of diatom populations, little is known about the molecular mechanisms of PCD triggered by different nutrient stresses. Here we describe the physiological, morphological, biochemical, and molecular changes in response to low levels of nutrients in the ubiquitous diatom Skeletonema marinoi The levels of gene expression involved in oxidation resistance and PCD strongly increased upon nitrogen (N) or phosphorus (P) starvation. The enzymatic activity of caspase 3-like protein also increased. Differences in mRNA levels and protein activities were observed between the low-N and low-P treatments, suggesting that PCD could have a differential response to different nutrient stresses. When cultures were replete with N or P, the growth inhibition stopped. Meanwhile, the enzymatic activity of caspase 3-like protein and the number of cells with damaged membranes decreased. These results suggest that PCD is an important cell fate decision mechanism in the marine diatom S. marinoi Our results provide important insight into how diatoms adjust phenotypic and genotypic features of their cell-regulated death programs when stressed by nutrient limitations. Overall, this study could allow us to better understand the molecular mechanism behind the formation and termination of diatom blooms in the marine environment.IMPORTANCE Our study showed how the ubiquitous diatom S. marinoi responded to different nutrient limitations with PCD in terms of physiological, morphological, biochemical, and molecular characteristics. Some PCD-related genes (PDCD4, GOX, and HSP90) induced by N deficiency were relatively upregulated compared to those induced by P deficiency. In contrast, the expression of the TSG101 gene in S. marinoi showed a clear and constant increase during P limitation compared to N limitation. These findings suggest that PCD is a complex mechanism involving several different proteins. The systematic mRNA level investigations provide new insight into understanding the oxidative stress- and cell death-related functional genes of diatoms involved in the response to nutrient fluctuations (N or P stress) in the marine environment.

Project description:BackgroundThe prognostic value of programmed cell death-ligand 1 (PD-L1) in gynecological cancers has been explored previously, but the conclusion remains controversial due to limited evidence. This study aimed to conduct an updated meta-analysis to re-investigate the predictive significance of PD-L1 expression.MethodsPubMed, EMBASE and Cochrane Library databases were searched. The associations between PD-L1 expression status and prognosis [overall survival (OS), progression-free survival (PFS), recurrence-free survival (RFS), cancer-specific survival (CSS) or disease-free survival (DFS)], clinical parameters [FIGO stage, lymph node metastasis (LNM), tumor size, infiltration depth, lymphovascular space invasion (LVSI) or grade] and response to anti-PD-1/PD-L1 treatment [objective response rate (ORR)] were analyzed by hazard ratios (HR) or relative risks (RR).ResultsFifty-five studies were enrolled. Overall, high PD-L1 expression was not significantly associated with OS, PFS, RFS, CSS and DFS of gynecological cancers. However, subgroup analysis of studies with reported HR (HR = 1.27) and a cut-off value of 5% (HR = 2.10) suggested that high PD-L1 expression was correlated with a shorter OS of gynecological cancer patients. Further sub-subgroup analysis revealed that high PD-L1 expressed on tumor-infiltrating immune cells (TICs) predicted a favorable OS for ovarian (HR = 0.72), but a poor OS for cervical cancer (HR = 3.44). PD-L1 overexpression was also correlated with a lower OS rate in non-Asian endometrial cancer (HR = 1.60). High level of PD-L1 was only clinically correlated with a shorter PFS in Asian endometrial cancer (HR = 1.59). Furthermore, PD-L1-positivity was correlated with LNM (for overall, ovarian and endometrial cancer expressed on tumor cells), advanced FIGO stage (for overall, ovarian cancer expressed on tumor cells, endometrial cancer expressed on tumor cells and TICs), LVSI (for overall and endometrial cancer expressed on tumor cells and TICs), and increasing infiltration depth/high grade (only for endometrial cancer expressed on TICs). Patients with PD-L1-positivity may obtain more benefit from anti-PD-1/PD-L1 treatment than the negative group, showing a higher ORR (RR = 1.98), longer OS (HR = 0.34) and PFS (HR = 0.61).ConclusionOur findings suggest high PD-L1 expression may be a suitable biomarker for predicting the clinical outcomes in patients with gynecological cancers.

Project description:BACKGROUND: Developmentally regulated programmed cell death (PCD) is the controlled death of cells that occurs throughout the life cycle of both plants and animals. The lace plant (Aponogeton madagascariensis) forms perforations between longitudinal and transverse veins in spaces known as areoles, via developmental PCD; cell death begins in the center of these areoles and develops towards the margin, creating a gradient of PCD. This gradient was examined using both long- and short-term live cell imaging, in addition to histochemical staining, in order to establish the order of cellular events that occur during PCD. RESULTS: The first visible change observed was the reduction in anthocyanin pigmentation, followed by initial chloroplast changes and the bundling of actin microfilaments. At this stage, an increased number of transvacuolar strands (TVS) was evident. Perhaps concurrently with this, increased numbers of vesicles, small mitochondrial aggregates, and perinuclear accumulation of both chloroplasts and mitochondria were observed. The invagination of the tonoplast membrane and the presence of vesicles, both containing organelle materials, suggested evidence for both micro- and macro-autophagy, respectively. Mitochondrial aggregates, as well as individual chloroplasts were subsequently seen undergoing Brownian motion in the vacuole. Following these changes, fragmentation of nuclear DNA, breakdown of actin microfilaments and early cell wall changes were detected. The vacuole then swelled, causing nuclear displacement towards the plasma membrane (PM) and tonoplast rupture followed closely, indicating mega-autophagy. Subsequent to tonoplast rupture, cessation of Brownian motion occurred, as well as the loss of mitochondrial membrane potential (??m), nuclear shrinkage and PM collapse. Timing from tonoplast rupture to PM collapse was approximately 20 minutes. The entire process from initial chlorophyll reduction to PM collapse took approximately 48 hours. Approximately six hours following PM collapse, cell wall disappearance began and was nearly complete within 24 hours. CONCLUSION: Results showed that a consistent sequence of events occurred during the remodelling of lace plant leaves, which provides an excellent system to study developmental PCD in vivo. These findings can be used to compare and contrast with other developmental PCD examples in plants.

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Computational analysis of dynamical responses to the intrinsic pathway of programmed cell death.

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Computational analysis of dynamical responses to the intrinsic pathway of programmed cell death.

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