MDM2 Overexpression, Activation of Signaling Networks, and Cell Proliferation

2014 ◽  
pp. 215-234 ◽  
Author(s):  
Swati Palit Deb ◽  
Shilpa Singh ◽  
Sumitra Deb
Keyword(s):  
Cell Proliferation ◽  
Signaling Networks ◽  
Mdm2 Overexpression

Targeting protein phosphatase PP2A for cancer therapy: development of allosteric pharmaceutical agents

2021 ◽  
Vol 135 (13) ◽  
pp. 1545-1556
Author(s):  
David L. Brautigan ◽  
Caroline Farrington ◽  
Goutham Narla
Keyword(s):  
Cell Proliferation ◽  
Protein Phosphatase ◽  
Signaling Networks ◽  
Survival Pathways ◽  
Novel Drugs ◽  
Phosphatase 2A ◽  
Therapy Development ◽  
Near Term ◽  
Small Molecule Modulators ◽  
Pharmaceutical Agents

Abstract Tumor initiation is driven by oncogenes that activate signaling networks for cell proliferation and survival involving protein phosphorylation. Protein kinases in these pathways have proven to be effective targets for pharmaceutical inhibitors that have progressed to the clinic to treat various cancers. Here, we offer a narrative about the development of small molecule modulators of the protein Ser/Thr phosphatase 2A (PP2A) to reduce the activation of cell proliferation and survival pathways. These novel drugs promote the assembly of select heterotrimeric forms of PP2A that act to limit cell proliferation. We discuss the potential for the near-term translation of this approach to the clinic for cancer and other human diseases.

Key Nodes In FLT3 Dependent Signaling Determine Growth and Survival Of Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2508-2508
Author(s):  
Kevin Dierck ◽  
Ina Siekmann ◽  
Sebastian Prall ◽  
Florian Beck ◽  
Irmela Jeremias ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Cell Proliferation ◽  
Acute Lymphoblastic Leukemia ◽  
Rna Interference ◽  
Tyrosine Kinase ◽  
Lymphoblastic Leukemia ◽  
Signaling Networks ◽  
Rtk Signaling

Abstract The balanced regulation of complex signaling networks plays an important role in cell proliferation, survival and apoptosis. Receptor tyrosine kinase (RTK) dependent signal transduction has been implicated in the pathogenesis of many malignancies including acute lymphoblastic leukemia (ALL) of childhood. Moreover, deregulated RTK activity was observed following targeted inhibition of constitutively active kinases or kinase-dependent pathways in a variety of malignancies, which conferred pharmacological resistance. In ALL, fms-like-tyrosine kinase 3 (FLT3) and platelet-derived growth factor receptor beta (PDGFRβ) are targeted for mutation (Roberts et al., 2012). However, in primary ALL the RTK dependent signaling state is poorly defined and the occurrence of relapse in the context of genotype-directed monotherapy regimens targeting RTKs, such as FLT3, underlines the need for an activity-based approach to RTK signaling in leukemia comprising the identification of critical downstream target proteins. To select for driver RTKs in ALL, we combined the analyses of RTK expression in primary ALL (n=102), ALL cell lines and normal hematopoietic cells with the characterization of ligand dependent cell proliferation as well as shRNA mediated RTK repression in vitro and in vivo. We observed aberrant RTK expression patterns in ALL cells compared to normal lymphoid progenitor and stem cell populations as well as mature T- and B-lymphocytes. RNA interference mediated repression of growth promoting RTKs FLT3 and PDGFRβ in primary ALL led to a loss or reduction of the affected cell population in vivo. To identify critical signaling nodes we performed a phosphoproteomic characterization by iTRAQ (isobaric tags for relative and absolute quantification)-based mass spectrometry of the signal transduction of selected driver RTKs in the corresponding primary ALL samples. Primary ALL cells were propagated in NSG mice after xenotransplantation, and regulated phosphoproteins were identified after ligand stimulation. Our network-directed approach to RTK signaling in ALL thus allowed for the identification of downstream signaling nodes implicated in aberrant RTK activity. We identified a total of 2241 phosphoproteins and observed a striking diversity of RTK driven signaling processes in primary ALL exhibiting only a marginal overlap between phosphoregulated proteins which illustrates the inter-individual heterogeneity and the challenge for non-combinatorial therapies. Despite a predominant receptor and cell type specific composition of potentiated signaling networks our phosphoproteomic analyses identified p21-activated protein kinase PAK2 as a novel key nodal point in FLT3 dependent signaling in ALL. The importance of PAK protein family members in the regulation of cell proliferation and survival and the emerging role of PAK proteins in the pathogenesis of a broad range of tumors suggests a hitherto unanticipated function in the malignant transformation of ALL and the signal transduction of FLT3 (Ye and Field, 2012). As a kinase PAK2 represents a druggable target and may be suited for combinatorial intervention strategies targeting FLT3 signaling in order to induce synthetic lethality. Inhibition of group I PAK kinases (PAK1, 2, 3) using the allosteric inhibitor IPA-3 and RNA interference mediated repression of PAK2 led to the loss of ALL cells due to an impaired cell proliferation and an increased apoptosis. Notably, PAK2 depleted ALL cells showed an elevated sensitivity towards pharmacological FLT3 inhibition which underlines the potential role of PAK2 as a novel target in ALL and the need for novel small molecule PAK inhibitors with higher specificity and improved applicability in vivo. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Signaling Networks That Link Cell Proliferation and Cell Fate

2002 ◽  
Vol 277 (14) ◽  
pp. 11617-11620 ◽  
Author(s):  
Rosalie C. Sears ◽  
Joseph R. Nevins
Keyword(s):  
Cell Proliferation ◽  
Cell Fate ◽  
Signaling Networks

scholarly journals MicroRNA-143 is Associated With Pathological Complete Response and Regulates Multiple Signaling Proteins in Breast Cancer

2019 ◽  
Vol 18 ◽  
pp. 153303381982730 ◽  
Author(s):  
Raúl García-Vázquez ◽  
Laurence A. Marchat ◽  
Erika Ruíz-García ◽  
Horacio Astudillo-de la Vega ◽  
Abelardo Meneses-García ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Neoadjuvant Therapy ◽  
Pathological Complete Response ◽  
Complete Response ◽  
Signaling Networks ◽  
Enzyme Linked Immunosorbent Assay ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Proliferation And Migration

Almost 55% to 80% of patients with breast cancer have an unfavorable pathological complete response to chemotherapy. MicroRNAs are small noncoding RNAs involved in cancer progression; however, their utility as predictors of pathological complete response to neoadjuvant chemotherapy is unclear. Here, we investigated if miR-143 could discriminate between pathological complete response and no-polymerase chain reaction of patients with locally advanced triple negative breast cancer that have received a fluorouracil-cisplatin/paclitaxel-based neoadjuvant treatment. Data showed that miR-143 exhibited a significant low expression ( P < .0006) in patients that achieved pathological complete response in comparison to nonresponder group. Receiver operating characteristic curve analysis suggested that miR-143 could be a good predictor of pathological complete response (area under curve = 0.849, P < .0006). Moreover, Kaplan-Meier analysis indicated that before neoadjuvant therapy low levels of miR-143 were associated to increased disease free survival. To gain insights into cellular functions of miR-143, we firstly showed that miR-143 was severely repressed in breast cancer cell lines and tumors in comparison to normal mammary cells and tissues. Ectopic restoration of miR-143 using RNA mimics inhibited both cell proliferation and migration and sensitized breast cancer cells to cisplatin therapy in vitro. To decipher the signaling networks regulated by miR-143, we used a high-throughput enzyme-linked immunosorbent assay-based phosphorylation antibody array. Phospho-proteomic profiling revealed that miR-143 coordinately reduced the protein levels and phosphorylation status of multiple oncoproteins involved in AKT, WNT/β-catenin, SAPK/JNK, FAK, and JAK/STAT signaling pathways. Moreover, low miR-143 and high GSK3-β, RAF1, paxillin, and p21CIP1 expression levels in a large cohort of patients with breast cancer were associated with worst outcome. In summary, miR-143 could be a potential predictor of response to neoadjuvant therapy and it may function as a divergent regulator of diverse signaling networks to suppress cell proliferation and migration in breast cancer.

scholarly journals Key signaling networks are dysregulated in patients with the adipose tissue disorder, lipedema

2021 ◽  
Author(s):  
Musarat Ishaq ◽  
Nadeeka Bandara ◽  
Steven Morgan ◽  
Cameron Nowell ◽  
Ahmad M. Mehdi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Transcriptional Profiling ◽  
Signaling Networks ◽  
Histone H2a ◽  
Significant Differential Expression ◽  
Functional Assays ◽  
Significant Impairment

Abstract Objectives Lipedema, a poorly understood chronic disease of adipose hyper-deposition, is often mistaken for obesity and causes significant impairment to mobility and quality-of-life. To identify molecular mechanisms underpinning lipedema, we employed comprehensive omics-based comparative analyses of whole tissue, adipocyte precursors (adipose-derived stem cells (ADSCs)), and adipocytes from patients with or without lipedema. Methods We compared whole-tissues, ADSCs, and adipocytes from body mass index–matched lipedema (n = 14) and unaffected (n = 10) patients using comprehensive global lipidomic and metabolomic analyses, transcriptional profiling, and functional assays. Results Transcriptional profiling revealed >4400 significant differences in lipedema tissue, with altered levels of mRNAs involved in critical signaling and cell function-regulating pathways (e.g., lipid metabolism and cell-cycle/proliferation). Functional assays showed accelerated ADSC proliferation and differentiation in lipedema. Profiling lipedema adipocytes revealed >900 changes in lipid composition and >600 differentially altered metabolites. Transcriptional profiling of lipedema ADSCs and non-lipedema ADSCs revealed significant differential expression of >3400 genes including some involved in extracellular matrix and cell-cycle/proliferation signaling pathways. One upregulated gene in lipedema ADSCs, Bub1, encodes a cell-cycle regulator, central to the kinetochore complex, which regulates several histone proteins involved in cell proliferation. Downstream signaling analysis of lipedema ADSCs demonstrated enhanced activation of histone H2A, a key cell proliferation driver and Bub1 target. Critically, hyperproliferation exhibited by lipedema ADSCs was inhibited by the small molecule Bub1 inhibitor 2OH-BNPP1 and by CRISPR/Cas9-mediated Bub1 gene depletion. Conclusion We found significant differences in gene expression, and lipid and metabolite profiles, in tissue, ADSCs, and adipocytes from lipedema patients compared to non-affected controls. Functional assays demonstrated that dysregulated Bub1 signaling drives increased proliferation of lipedema ADSCs, suggesting a potential mechanism for enhanced adipogenesis in lipedema. Importantly, our characterization of signaling networks driving lipedema identifies potential molecular targets, including Bub1, for novel lipedema therapeutics.

Fibroblasts During Hypertrophic Scar Formation and Resolution

1973 ◽  
Vol 31 ◽  
pp. 428-429
Author(s):  
C. W. Kischer
Keyword(s):  
Electron Microscopy ◽  
Scanning Electron Microscopy ◽  
Cell Proliferation ◽  
Fine Structure ◽  
Metabolic Activity ◽  
Hypertrophic Scar ◽  
Normal Skin ◽  
Ground Substance ◽  
Hypertrophic Scars ◽  
Scanning Electron

The morphology of the fibroblasts changes markedly as the healing period from burn wounds progresses, through development of the hypertrophic scar, to resolution of the scar by a self-limiting process of maturation or therapeutic resolution. In addition, hypertrophic scars contain an increased cell proliferation largely made up of fibroblasts. This tremendous population of fibroblasts seems congruous with the abundance of collagen and ground substance. The fine structure of these cells should reflect some aspects of the metabolic activity necessary for production of the scar, and might presage the stage of maturation.A comparison of the fine structure of the fibroblasts from normal skin, different scar types, and granulation tissue has been made by transmission (TEM) and scanning electron microscopy (SEM).

The Effect of Androgen Depletion and Replacement on the Epithelium of the Seminal Vesicle of the Aging Rat

1975 ◽  
Vol 33 ◽  
pp. 590-591
Author(s):  
Venita F. Allison
Keyword(s):  
Cell Proliferation ◽  
Seminal Vesicle ◽  
Male Rats ◽  
Target Cells ◽  
Cell Regeneration ◽  
Secretory Function ◽  
Electron Microscopic ◽  
Aging Rat ◽  
Microscopic Studies ◽  
Androgen Depletion

In 1930, Moore, Hughes and Gallager reported that after castration seminal vesicle epithelial cell atrophy occurred and that cell regeneration could be achieved with daily injections of testis extract. Electron microscopic studies have confirmed those observations and have shown that testosterone injections restore the epithelium of the seminal vesicle in adult castrated male rats. Studies concerned with the metabolism of androgens point out that dihydrotestosterone stimulates cell proliferation and that other metabolites of testosterone probably influence secretory function in certain target cells.Although the influence of androgens on adult seminal vesicle epithelial cytology is well documented, little is known of the effect of androgen depletion and replacement on those cells in aging animals. The present study is concerned with the effect of castration and testosterone injection on the epithelium of the seminal vesicle of aging rats.

Acetaminophen: Macula densa hypersecretory activity by induced hepatotoxicity

1987 ◽  
Vol 45 ◽  
pp. 934-935
Author(s):  
S.S. Poolsawat ◽  
C.A. Huerta ◽  
S.TY. Lae ◽  
G.A. Miranda
Keyword(s):  
Cell Proliferation ◽  
Liver Function ◽  
Chronic Inflammation ◽  
Foam Cell ◽  
Term Effect ◽  
Short Term ◽  
Drug Induced ◽  
Experimental Induction ◽  
Tissue Alterations ◽  
Toxic Responses

Introduction. Experimental induction of altered histology by chemical toxins is of particular importance if its outcome resembles histopathological phenomena. Hepatotoxic drugs and chemicals are agents that can be converted by the liver into various metabolites which consequently evoke toxic responses. Very often, these drugs are intentionally administered to resolve an illness unrelated to liver function. Because of hepatic detoxification, the resulting metabolites are suggested to be integrated into the macromolecular processes of liver function and cause an array of cellular and tissue alterations, such as increased cytoplasmic lysis, centrilobular and localized necroses, chronic inflammation and “foam cell” proliferation of the hepatic sinusoids (1-4).Most experimentally drug-induced toxicity studies have concentrated primarily on the hepatic response, frequently overlooking other physiological phenomena which are directly related to liver function. Categorically, many studies have been short-term effect investigations which seldom have followed up the complications to other tissues and organs when the liver has failed to function normally.

Cdh1, the anaphase promoting complex or cyclosome (APC/C) cofactor, inhibits trophoblast cell proliferation and invasion

2010 ◽  
Vol 34 (8) ◽  
pp. S10-S10
Author(s):  
Baoping Zhang ◽  
Jing Peng ◽  
Li Zhang ◽  
Hong Xu ◽  
Haibin Kuang
Keyword(s):  
Cell Proliferation ◽  
Trophoblast Cell ◽  
Anaphase Promoting Complex ◽  
Proliferation And Invasion

EMBJ08, a novel gene promoting cell proliferation

2010 ◽  
Vol 34 (8) ◽  
pp. S50-S50
Author(s):  
Jing Li ◽  
Dongxia Hao ◽  
Weiwei Deng ◽  
Na Li ◽  
Shai Guo ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Novel Gene
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