scholarly journals Oxygen-responsive p53 tetramer-octamer switch controls cell fate

2019 ◽  
Author(s):  
Shashank Taxak ◽  
Uttam Pati
Keyword(s):  
Decision Making ◽  
Tumor Suppressor ◽  
Solid Tumors ◽  
Cell Fate ◽  
Control Cell ◽  
Reverse Direction ◽  
Gain Of Function ◽  
Flip Flop ◽  
In Cells

ABSTRACTSolid tumors require an efficient decision-making mechanism to progress through a gradient of hypoxia. Here, we show that an oxygen-sensory p53 tetramer-octamer switch makes cell decision for survival or death in variable hypoxia. Trapping homo-oligomers from biosynthesis cycle, we found a metastable p53 tetramer in cells. Under the operation of switch, tetramer segregates the p53 character of a tumor suppressor and promoter. The p53 switch generates a pattern of its on-off state in time that is specific to the strength of hypoxia. A bidirectional tetramer-octamer conversion in on state decides the restoration of basal state by forward and programs apoptosis upon the reverse shift via p53-MDM2 loop. However, reversible dimertetramer transitions in off state trigger chaperoning of HIF-1 complex by tetramer in forward and oncogenic gain-of-function by prion-like dimers in reverse direction. Temporal on-off patterns calibrate stabilized p53 pool by defining the abundance of dimer, tetramer and octamer that ultimately decides diverse cellular outcomes in hypoxia. Through multi-chromophore FRET, we further show that chaperoning of HIF-1 may modulate angiogenesis through a possible flip-flop of the p53T-HIF-1 complex upon DNA. Our results demonstrate how p53 can sense oxygen and act upon its homo-oligomerization states to control cell fate in hypoxic tumors.

iTSP-PseAAC: Identify Tumor Suppressor Proteins by Using Fully Connected Neural Network and PseAAC

2021 ◽  
Vol 15 ◽  
Author(s):  
Muhammad Awais ◽  
Waqar Hussain ◽  
Nouman Rasool ◽  
Yaser Daanial Khan
Keyword(s):  
Tumor Suppressor ◽  
Cross Validation ◽  
Control Cell ◽  
Normal Function ◽  
In Vivo Studies ◽  
Tumor Suppressor Proteins ◽  
Proposed Model ◽  
Self Consistency

Background: The uncontrolled growth due to accumulation of genetic and epigenetic changes as a result of loss or reduction in the normal function of Tumor Suppressor Genes (TSGs) and Pro-oncogenes is known as cancer. TSGs control cell division and growth by repairing of DNA mistakes during replication and restrict the unwanted proliferation of a cell or activities, those are the part of tumor production. Objectives: This study aims to propose a novel, accurate, user-friendly model to predict tumor suppressor proteins, which would be freely available to experimental molecular biologists to assist them using in vitro and in vivo studies. Methods: The predictor model has used the input feature vector (IFV) calculated from the physicochemical properties of proteins based on FCNN to compute the accuracy, sensitivity, specificity, and MCC. The proposed model was validated against different exhaustive validation techniques i.e. self-consistency and cross-validation. Results: Using self-consistency, the accuracy is 99%, for cross-validation and independent testing has 99.80% and 100% accuracy respectively. The overall accuracy of the proposed model is 99%, sensitivity value 98% and specificity 99% and F1-score was 0.99. Conclusion: It concludes, the proposed model for prediction of the tumor suppressor proteins can predict the tumor suppressor proteins efficiently, but it still has space for improvements in computational ways as the protein sequences may rapidly increase, day by day.

scholarly journals Drosophila Notch receptor activity suppresses Hairless function during adult external sensory organ development.

Genetics ◽  
1995 ◽  
Vol 141 (4) ◽  
pp. 1491-1505
Author(s):  
D F Lyman ◽  
B Yedvobnick
Keyword(s):  
Cell Fate ◽  
Daughter Cell ◽  
Notch Receptor ◽  
Sensory Organ ◽  
Cell Fates ◽  
Gain Of Function ◽  
Over Expression ◽  
Cell Fate Decisions ◽  
Synergistic Enhancement ◽  
Conditional Expression

Abstract The neurogenic Notch locus of Drosophila encodes a receptor necessary for cell fate decisions within equivalence groups, such as proneural clusters. Specification of alternate fates within clusters results from inhibitory communication among cells having comparable neural fate potential. Genetically, Hairless (H) acts as an antagonist of most neurogenic genes and may insulate neural precursor cells from inhibition. H function is required for commitment to the bristle sensory organ precursor (SOP) cell fate and for daughter cell fates. Using Notch gain-of-function alleles and conditional expression of an activated Notch transgene, we show that enhanced signaling produces H-like loss-of-function phenotypes by suppressing bristle SOP cell specification or by causing an H-like transformation of sensillum daughter cell fates. Furthermore, adults carrying Notch gain of function and H alleles exhibit synergistic enhancement of mutant phenotypes. Over-expression of an H+ transgene product suppressed virtually all phenotypes generated by Notch gain-of-function genotypes. Phenotypes resulting from over-expression of the H+ transgene were blocked by the Notch gain-of-function products, indicating a balance between Notch and H activity. The results suggest that H insulates SOP cells from inhibition and indicate that H activity is suppressed by Notch signaling.

scholarly journals Identification and Characterization of Genes That Interact With lin-12 in Caenorhabditis elegans

Genetics ◽  
1997 ◽  
Vol 147 (4) ◽  
pp. 1675-1695 ◽  
Author(s):  
Frans E Tax ◽  
James H Thomas ◽  
Edwin L Ferguson ◽  
H Robert Horvitzt
Keyword(s):  
Cell Fate ◽  
Low Frequency ◽  
Signal Transduction Pathway ◽  
Temperature Shift ◽  
Egg Laying ◽  
Null Alleles ◽  
Temperature Sensitive ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Suppressor Mutations

Abstract We identified and characterized 14 extragenic mutations that suppressed the dominant egg-laying defect of certain lin-12 gain-of-function mutations. These suppressors defined seven genes: sup-l7, lag-2, sel-4, sel-5, sel-6, sel-7 and sel-8. Mutations in six of the genes are recessive suppressors, whereas the two mutations that define the seventh gene, lag-2, are semi-dominant suppressors. These suppressor mutations were able to suppress other lin-12 gain-of-function mutations. The suppressor mutations arose at a very low frequency per gene, 10-50 times below the typical loss-of-function mutation frequency. The suppressor mutations in sup1 7 and lag-2 were shown to be rare non-null alleles, and we present evidence that null mutations in these two genes cause lethality. Temperature-shift studies for two suppressor genes, sup1 7and lag-2, suggest that both genes act at approximately the same time as lin-12in specifying a cell fate. Suppressor alleles of six of these genes enhanced a temperature-sensitive loss-of-function allele of glp-1, a gene related to lin-12 in structure and function. Our analysis of these suppressors suggests that the majority of these genes are part of a shared lin-12/glp-1 signal transduction pathway, or act to regulate the expression or stability of lin-12 and glp-1.

scholarly journals A Gain-of-Function Screen for Genes That Affect the Development of the Drosophila Adult External Sensory Organ

Genetics ◽  
2000 ◽  
Vol 155 (2) ◽  
pp. 733-752 ◽  
Author(s):  
Salim Abdelilah-Seyfried ◽  
Yee-Ming Chan ◽  
Chaoyang Zeng ◽  
Nicholas J Justice ◽  
Susan Younger-Shepherd ◽  
...  
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Cell Fate ◽  
P Element ◽  
External Support ◽  
Sensory Organ ◽  
Sensory Organs ◽  
Gain Of Function ◽  
Asymmetric Cell Divisions ◽  
Single Precursor

Abstract The Drosophila adult external sensory organ, comprising a neuron and its support cells, is derived from a single precursor cell via several asymmetric cell divisions. To identify molecules involved in sensory organ development, we conducted a tissue-specific gain-of-function screen. We screened 2293 independent P-element lines established by P. Rørth and identified 105 lines, carrying insertions at 78 distinct loci, that produced misexpression phenotypes with changes in number, fate, or morphology of cells of the adult external sensory organ. On the basis of the gain-of-function phenotypes of both internal and external support cells, we subdivided the candidate lines into three classes. The first class (52 lines, 40 loci) exhibits partial or complete loss of adult external sensory organs. The second class (38 lines, 28 loci) is associated with increased numbers of entire adult external sensory organs or subsets of sensory organ cells. The third class (15 lines, 10 loci) results in potential cell fate transformations. Genetic and molecular characterization of these candidate lines reveals that some loci identified in this screen correspond to genes known to function in the formation of the peripheral nervous system, such as big brain, extra macrochaetae, and numb. Also emerging from the screen are a large group of previously uncharacterized genes and several known genes that have not yet been implicated in the development of the peripheral nervous system.

scholarly journals Notch signaling coordinates ommatidial rotation in the Drosophila eye via transcriptional regulation of the EGF-Receptor ligand Argos

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yildiz Koca ◽  
Benjamin E. Housden ◽  
William J. Gault ◽  
Sarah J. Bray ◽  
Marek Mlodzik
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Planar Cell Polarity ◽  
Egf Receptor ◽  
Control Cell ◽  
Loss Of Function ◽  
Egfr Signaling ◽  
Specific Expression ◽  
Egfr Signaling Pathway ◽  
Ommatidial Rotation

AbstractIn all metazoans, a small number of evolutionarily conserved signaling pathways are reiteratively used during development to orchestrate critical patterning and morphogenetic processes. Among these, Notch (N) signaling is essential for most aspects of tissue patterning where it mediates the communication between adjacent cells to control cell fate specification. In Drosophila, Notch signaling is required for several features of eye development, including the R3/R4 cell fate choice and R7 specification. Here we show that hypomorphic alleles of Notch, belonging to the Nfacet class, reveal a novel phenotype: while photoreceptor specification in the mutant ommatidia is largely normal, defects are observed in ommatidial rotation (OR), a planar cell polarity (PCP)-mediated cell motility process. We demonstrate that during OR Notch signaling is specifically required in the R4 photoreceptor to upregulate the transcription of argos (aos), an inhibitory ligand to the epidermal growth factor receptor (EGFR), to fine-tune the activity of EGFR signaling. Consistently, the loss-of-function defects of Nfacet alleles and EGFR-signaling pathway mutants are largely indistinguishable. A Notch-regulated aos enhancer confers R4 specific expression arguing that aos is directly regulated by Notch signaling in this context via Su(H)-Mam-dependent transcription.

scholarly journals Cyto-friendly polymerization at cell surfaces modulates cell fate by clustering cell-surface receptors

2020 ◽  
Vol 11 (16) ◽  
pp. 4221-4225 ◽  
Author(s):  
Jing Qi ◽  
Weishuo Li ◽  
Xiaoling Xu ◽  
Feiyang Jin ◽  
Di Liu ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cell Fate ◽  
Cell Surface Receptors ◽  
Cell Surfaces ◽  
Receptor Clustering ◽  
Surface Polymerization ◽  
Surface Receptors ◽  
Anti Cd20 ◽  
In Cells

Cell-surface polymerization of anti-CD20 aptamer modified macromer to induce CD20 receptor clustering, and effectively initiate the apoptotic signals in cells.

scholarly journals Positive Feedback Between PU.1 and the Cell Cycle Controls Myeloid Differentiation

Science ◽  
2013 ◽  
Vol 341 (6146) ◽  
pp. 670-673 ◽  
Author(s):  
Hao Yuan Kueh ◽  
Ameya Champhekar ◽  
Stephen L. Nutt ◽  
Michael B. Elowitz ◽  
Ellen V. Rothenberg
Keyword(s):  
Cell Cycle ◽  
Cell Fate ◽  
Positive Feedback ◽  
Regulatory Gene ◽  
Control Cell ◽  
Stem Cell Differentiation ◽  
Myeloid Differentiation ◽  
Cycle Duration ◽  
Gene Circuits ◽  
Cell Cycles

Regulatory gene circuits with positive-feedback loops control stem cell differentiation, but several mechanisms can contribute to positive feedback. Here, we dissect feedback mechanisms through which the transcription factor PU.1 controls lymphoid and myeloid differentiation. Quantitative live-cell imaging revealed that developing B cells decrease PU.1 levels by reducing PU.1 transcription, whereas developing macrophages increase PU.1 levels by lengthening their cell cycles, which causes stable PU.1 accumulation. Exogenous PU.1 expression in progenitors increases endogenous PU.1 levels by inducing cell cycle lengthening, implying positive feedback between a regulatory factor and the cell cycle. Mathematical modeling showed that this cell cycle–coupled feedback architecture effectively stabilizes a slow-dividing differentiated state. These results show that cell cycle duration functions as an integral part of a positive autoregulatory circuit to control cell fate.

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