The Involvement of Cellular ras in Proliferative Signaling

1993 ◽  
pp. 301-321
Author(s):  
D. W. Stacey
Keyword(s):  
Proliferative Signaling

scholarly journals The biogenesis and biological function of PIWI-interacting RNA in cancer

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Silu Chen ◽  
Shuai Ben ◽  
Junyi Xin ◽  
Shuwei Li ◽  
Rui Zheng ◽  
...  
Keyword(s):  
Cancer Diagnosis ◽  
Precancerous Lesions ◽  
Biological Activities ◽  
Cancer Hallmarks ◽  
Diagnosis And Prognosis ◽  
Small Ncrnas ◽  
Bioinformatics Databases ◽  
Non Coding Rnas ◽  
Underlying Mechanisms ◽  
Proliferative Signaling

AbstractSmall non-coding RNAs (ncRNAs) are vital regulators of biological activities, and aberrant levels of small ncRNAs are commonly found in precancerous lesions and cancer. PIWI-interacting RNAs (piRNAs) are a novel type of small ncRNA initially discovered in germ cells that have a specific length (24–31 nucleotides), bind to PIWI proteins, and show 2′-O-methyl modification at the 3′-end. Numerous studies have revealed that piRNAs can play important roles in tumorigenesis via multiple biological regulatory mechanisms, including silencing transcriptional and posttranscriptional gene processes and accelerating multiprotein interactions. piRNAs are emerging players in the malignant transformation of normal cells and participate in the regulation of cancer hallmarks. Most of the specific cancer hallmarks regulated by piRNAs are involved in sustaining proliferative signaling, resistance to cell death or apoptosis, and activation of invasion and metastasis. Additionally, piRNAs have been used as biomarkers for cancer diagnosis and prognosis and have great potential for clinical utility. However, research on the underlying mechanisms of piRNAs in cancer is limited. Here, we systematically reviewed recent advances in the biogenesis and biological functions of piRNAs and relevant bioinformatics databases with the aim of providing insights into cancer diagnosis and clinical applications. We also focused on some cancer hallmarks rarely reported to be related to piRNAs, which can promote in-depth research of piRNAs in molecular biology and facilitate their clinical translation into cancer treatment.

scholarly journals Complex CSF3R Protein Isoform Interactions Dictate Cytokine Responsiveness

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-35
Author(s):  
Sara L. Seegers ◽  
Amanda Lance ◽  
Lawrence J Druhan ◽  
Belinda R Avalos
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Splice Variant ◽  
Splice Variants ◽  
Polyclonal Antibodies ◽  
Human Cells ◽  
Dependent Manner ◽  
Epitope Tag ◽  
Proliferative Signaling ◽  
Primary Human Cells

CSF3R, the receptors for granulocyte colony stimulating factor, is a critical regulator of neutrophil production. Multiple CSF3R mRNA transcripts have been identified and are annotated in Genbank. The expression and function of the different CSF3R proteins have not been fully elucidated. We generated antibodies specific for two of the identified and annotated isoforms, V3 and V4. CSF3R-V4 is a truncated variant of V1 with a unique C-terminal 34 amino acids and this variant confers enhanced growth signals. Changes in the ratio of V1:V4 isoforms have been implicated in chemotherapy resistance and relapse of AML. CSF3R-V3 is a variant of V1 with a 27 amino acid insertion between two conserved domains in the cytoplasmic portion of the receptor involved in JAK/STAT activation, termed the box 1 and box 2. CSF3R-V3 produces reduced proliferative signaling in response to G-CSF. When V3 is co-expressed with V1, proliferative signaling is reduced in a concentration dependent manner. In order to generate custom rabbit polyclonal antibodies specific for CSF3R-V3 and CSF3R-V4 we used either a peptide that corresponds to a unique amino acid sequence present only in CSF3R-V3 or a peptide specific for a portion of the C-terminal amino acid sequence unique to the CSF3R-V4 isoform conjugated to an immunogenic carrier protein. These immunogens both produced robust immune responses, and the polyclonal antibodies were subsequently purified from bulk sera. Immunoblot analysis of lysates from Ba/F3 cells expressing CSF3R-V1 (V1), CSF3R-V3 (V3), or CSF3R-V4 (V4) demonstrated that both the custom generated anti-CSF3R-V3 and anti-CSF3R-V4 antibodies were very specific, recognizing only the appropriate CSF3R receptor isoform. All three CSF3R splice variants are recognized by commercially available anti-CSF3R (clone LMM741 to CD114), while the anti-CSF3R-V4 custom antibody and the custom anti-CSF3R-V3 antibody recognizes only the CSF3R-V4 and CSF3R-V3 isoforms, respectively. We next sought to detect the CSF3R receptor isoforms in primary human cells. Using our custom antibodies, we detected for the first time, both the CSF3R-V3 and CSF3R-V4 receptor forms in primary neutrophils isolated from healthy donors. Each of the CSF3R isoforms produce unique signaling, and we hypothesized that the observed differences in G-CSF-dependent signaling is produced by the expression level of each receptor isoform via both homodimerization and by heterodimerization of the receptor splice variant proteins. To investigate the potential for heterodimerization of the CSF3R-V1 with the V3 and V4 isoforms, we generated a CSF3R-V1 with a c-terminal epitope tag and co-expressed this construct with both CSF3R-V3 or CSF3R-V4. Immunoprecipitation with an antibody to the epitope tag (recognizing the V1 variant) followed by immunoblotting with the custom anti-V3 or anti-V4 antibodies demonstrated that both CSF3R-V3 and CSF3R-V4 co-immunoprecipitated with CSF3R-V1, in agreement with our hypothesis that the splice variants form receptor heterodimers. Of note, the CSF3R receptor heterodimers are detected even in the absence of G-CSF, thus demonstrating that CSF3R exist as a preformed receptor dimer in an inactive state. In conclusion, we have generated antibodies that specifically detect the CSF3R-V3 and the CSF3R-V4 receptor proteins. These are the first studies to demonstrate the expression of the CSF3R splice variants at the protein level, in both cell lines and primary human cells. In addition, these are the first studies to demonstrate the formation of heterodimers of the CSF3R splice variants, providing a mechanism for the observed alteration in ligand-dependent signaling produced under conditions of altered splice variant expression. Disclosures Avalos: Juno: Membership on an entity's Board of Directors or advisory committees; Best Practice-Br Med J: Patents & Royalties: receives royalties from a coauthored article on evaluation of neutropenia.

scholarly journals Gαs promotes EEA1 endosome maturation and shuts down proliferative signaling through interaction with GIV (Girdin)

2012 ◽  
Vol 23 (23) ◽  
pp. 4623-4634 ◽  
Author(s):  
Anthony O. Beas ◽  
Vanessa Taupin ◽  
Carmen Teodorof ◽  
Lien T. Nguyen ◽  
Mikel Garcia-Marcos ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Egfr Signaling ◽  
Early Endosomes ◽  
Epidermal Growth ◽  
Survival Signaling ◽  
Endosome Maturation ◽  
Proliferative Signaling

The organization of the endocytic system into biochemically distinct subcompartments allows for spatial and temporal control of the strength and duration of signaling. Recent work has established that Akt cell survival signaling via the epidermal growth factor receptor (EGFR) occurs from APPL early endosomes that mature into early EEA1 endosomes. Less is known about receptor signaling from EEA1 endosomes. We show here that EGF-induced, proliferative signaling occurs from EEA1 endosomes and is regulated by the heterotrimeric G protein Gαs through interaction with the signal transducing protein GIV (also known as Girdin). When Gαs or GIV is depleted, activated EGFR and its adaptors accumulate in EEA1 endosomes, and EGFR signaling is prolonged, EGFR down-regulation is delayed, and cell proliferation is greatly enhanced. Our findings define EEA1 endosomes as major sites for proliferative signaling and establish that Gαs and GIV regulate EEA1 but not APPL endosome maturation and determine the duration and strength of proliferative signaling from this compartment.

Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBPα expression

Blood ◽  
2004 ◽  
Vol 103 (5) ◽  
pp. 1883-1890 ◽  
Author(s):  
Rui Zheng ◽  
Alan D. Friedman ◽  
Mark Levis ◽  
Li Li ◽  
Edward G. Weir ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Tandem Duplication ◽  
Myeloid Differentiation ◽  
Internal Tandem Duplication ◽  
Activating Mutations ◽  
Flt3 Inhibitor ◽  
Enhancer Binding Protein ◽  
Differentiation Block ◽  
Proliferative Signaling

AbstractConstitutively activating mutations of FMS-like tyrosine kinase 3 (FLT3) occur in approximately one third of patients with acute myeloid leukemia (AML) and are associated with poor prognosis. Altered FLT3 signaling leads to antiapoptotic and proliferative signaling pathways. We recently showed that these mutations can also contribute to the differentiation arrest that characterizes leukemia. In this report we investigated the mechanism by which internal tandem duplication (ITD) mutation of FLT3 signaling blocks differentiation. Normally, myeloid differentiation requires the induction of CCAAT/enhancer-binding protein α (C/EBPα) and PU.1 expression. Expression of both genes was repressed by FLT3/ITD signaling in 32Dcl3 (32D) cells and this repression was overcome by treatment with a FLT3 inhibitor, allowing differentiation to proceed. We also observed increased expression of C/EBPα and PU.1 accompanied by signs of differentiation in 2 of 3 primary AML samples from patients with FLT3/ITD mutations receiving a FLT3 inhibitor, CEP-701, as part of a clinical trial. Forced expression of C/EBPα was also able to overcome FLT3/ITD-mediated differentiation block, further proving the importance of C/EBPα in this process.

scholarly journals Proliferative signaling initiated in ACTH receptors

2000 ◽  
Vol 33 (10) ◽  
pp. 1133-1140 ◽  
Author(s):  
C.F.P. Lotfi ◽  
A.P. Lepique ◽  
F.L. Forti ◽  
T.T. Schwindt ◽  
C.B. Eichler ◽  
...  
Keyword(s):  
Proliferative Signaling

scholarly journals AKR1C3 Inhibitory Potency of Naturally-occurring Amaryllidaceae Alkaloids of Different Structural Types

2017 ◽  
Vol 12 (2) ◽  
pp. 1934578X1701200 ◽  
Author(s):  
Daniela Hulcová ◽  
Kateřina Breiterová ◽  
Lucie Zemanová ◽  
Tomáš Siatka ◽  
Marcela Šafratová ◽  
...  
Keyword(s):  
Isoquinoline Alkaloid ◽  
Inhibitory Potency ◽  
Amaryllidaceae Alkaloids ◽  
Naturally Occurring ◽  
Pathological Conditions ◽  
Model Substance ◽  
Inhibition Potency ◽  
Further Development ◽  
Related Compounds ◽  
Proliferative Signaling

Aldo-keto reductase 1C3 (AKR1C3) is an important human enzyme that participates in the reduction of steroids and prostaglandins, which leads to proliferative signaling. AKR1C3 is frequently upregulated in various cancers, and this enzyme has been suggested as a therapeutic target for the treatment of these pathological conditions. The fact that the isoquinoline alkaloid stylopine has been identified as a potent AKR1C3 inhibitor has prompted us to screen a library of diverse types of Amaryllidaceae alkaloids, which biogenetically are isoquinoline alkaloids, on a recombinant form of AKR1C3. From the tested compounds, only tazettine showed moderate AKR1C3 inhibitory potency with an IC50 value of 15.8 ± 1.2 μM. Tazettine is a common Amaryllidaceae alkaloid, which could be used as a model substance for the further development of either analogues or related compounds with better inhibition potency.

scholarly journals Small Molecule ErbB Inhibitors Decrease Proliferative Signaling and Promote Apoptosis in Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

PLoS ONE ◽  
2013 ◽  
Vol 8 (8) ◽  
pp. e70608 ◽  
Author(s):  
Mary E. Irwin ◽  
Laura D. Nelson ◽  
Janice M. Santiago-O’Farrill ◽  
Phillip D. Knouse ◽  
Claudia P. Miller ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Small Molecule ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Proliferative Signaling ◽  
Philadelphia Chromosome Positive

scholarly journals Involvement of Shc and Cbl-PI 3-kinase in Lyn-dependent proliferative signaling pathways for G-CSF

Oncogene ◽  
2000 ◽  
Vol 19 (1) ◽  
pp. 97-105 ◽  
Author(s):  
Anatoly Grishin ◽  
Srish Sinha ◽  
Vera Roginskaya ◽  
Michael J Boyer ◽  
Julian Gomez-Cambronero ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Proliferative Signaling
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