A role for substance P in cancer promotion and progression: a mechanism to counteract intracellular death signals following oncogene activation or DNA damage

2006 ◽  
Vol 25 (1) ◽  
pp. 137-145 ◽  
Author(s):  
F. Esteban ◽  
M. Muñoz ◽  
M. A. González-Moles ◽  
M. Rosso
Keyword(s):  
Dna Damage ◽  
Substance P ◽  
Oncogene Activation ◽  
Death Signals

scholarly journals MICRORNA REGULATORS OF THE SENESCENCE TRANSCRIPTOME

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S835-S835
Author(s):  
O’Wayne Rodney ◽  
Myriam Gorospe ◽  
Kotb Abdelmohsen
Keyword(s):  
Dna Damage ◽  
Cellular Senescence ◽  
Growth Arrest ◽  
Proliferating Cells ◽  
Telomere Shortening ◽  
Qpcr Analysis ◽  
Oncogene Activation ◽  
Dna Foci ◽  
Transcriptome Signature

Abstract Cellular senescence is a state of indefinite growth arrest triggered in response to sublethal stresses such as telomere shortening, DNA damage, oxidative injury, oncogene activation, and hypoxia. Compared with proliferating cells, senescent cells are enlarged, display heterochromatic DNA foci, and express distinct subsets of proteins, including the enzyme β-galactosidase (β-gal). Previously, we identified transcriptome signature of senescent cells. We asked if these transcripts might be regulated by microRNAs (miRNAs). To address this question, we identified six miRNAs (miR-129-5p, -19a-3p, -128-3p, -124-3p, -340-5p, and -27b-3p) as potential regulators of subsets of transcripts differentially expressed during senescence. RT-qPCR analysis indicated that miR-129-5p, -19a-3p, -128-3p, -124-3p, and -340-5p were downregulated in senescent cells. We modulated these miRNAs in proliferating WI-38 fibroblasts and found that miRNA antagomirs did not show significant changes in β-gal activity. Interestingly, however, overexpression of miR-124-3p or miR-340-5p increased β-gal activity. We conclude that despite the decrease of miR-124-3p and miR-340-5p in senescent cells, their overexpression enhanced senescence as indicated by β-gal activity. Future analyses will focus on the mechanisms through which these miRNAs induce senescence and their physiologic and pathologic impacts in vivo.

Replicative senescence as a barrier to human cancer

2000 ◽  
Vol 28 (2) ◽  
pp. 226-233 ◽  
Author(s):  
E. K. Parkinson ◽  
J. Munro ◽  
K. Steeghs ◽  
V. Morrison ◽  
H. Ireland ◽  
...  
Keyword(s):  
Dna Damage ◽  
Replicative Senescence ◽  
Human Cancer ◽  
Cell Cycle Checkpoint ◽  
P16 Protein ◽  
Normal Keratinocytes ◽  
Oncogene Activation ◽  
Cycle Checkpoint ◽  
P53 Activation ◽  
Dependent Mechanism

There is evidence that one critically short telomere may be recognized as DNA damage and, as a consequence, induce a p53/p21WAF- and pl6INK4A-dependent G1 cell cycle checkpoint to cause senescence. Additionally, senescence via a p53-and pl6INK4A-dependent mechanism can be induced by the over- or under-stimulation of certain signalling pathways that are involved in cancer. Central to this alternative senescence mechanism is the pl4ARF protein, which connects oncogene activation, but not DNA damage, to p53 activation and senescence. We find that immortal keratinocytes almost invariably have dysfunctional p53 and p16 and have high levels of telomerase, but very often express a wild-type pl4ARF. Furthermore, when normal keratinocytes senesce they show a striking elevation of p16 protein, but not of p14ARF or its downstream targets p53 and p21WAF. These results suggest that p16, rather than pl4ARF, is the more important gene in human keratinocyte senescence, but do not exclude a co-operative role for pl4ARF, perhaps in the induction of senescence by activated oncogenes in neoplasia. Regardless of mechanism, these results suggest that replicative senescence acts as a barrier to human cancer development.

scholarly journals A human cellular sequence implicated in trk oncogene activation is DNA damage inducible.

1990 ◽  
Vol 87 (16) ◽  
pp. 6039-6043 ◽  
Author(s):  
R. Ben-Ishai ◽  
R. Scharf ◽  
R. Sharon ◽  
I. Kapten
Keyword(s):  
Dna Damage ◽  
Oncogene Activation ◽  
Cellular Sequence

Guardians of cell death: the Bcl-2 family proteins

2003 ◽  
Vol 39 ◽  
pp. 73-88 ◽  
Author(s):  
Peter T Daniel ◽  
Klaus Schulze-Osthoff ◽  
Claus Belka ◽  
Dilek Güner
Keyword(s):  
Dna Damage ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Small Molecules ◽  
Death Receptors ◽  
Amino Acid Sequence Homology ◽  
The Family ◽  
Dna Damage Signalling ◽  
Functional Analyses ◽  
Death Signals

Apoptosis is mediated through at least three major pathways that are regulated by (i) the death receptors, (ii) the mitochondria and (iii) the ER (endoplasmic reticulum). In most cells, these pathways are controlled by the Bcl-2 family of proteins that can be divided into anti-apoptotic and pro-apoptotic members. Although the overall amino acid sequence homology between the family members is relatively low, they contain highly conserved domains, referred to as BH (Bcl-2 homology) domains (BH1-4), that are essential for homo- and hetero-complex formation, as well as for their cell-death-inducing capacity. Structural and functional analyses revealed that the pro-apoptotic homologues can be subdivided into the Bax subfamily and the growing BH3-only subfamily. Recent data indicate that BH3-only proteins act as mediators that link various upstream signals, including death receptors and DNA damage signalling, to the mitochondrial and the ER pathway. This review discusses recent structural and functional insights into how these subfamilies promote or inhibit cell-death signals, and how these properties may be utilized for development of apoptosis-promoting small molecules, e.g. in cancer therapy.

scholarly journals NMI mediates transcription-independent ARF regulation in response to cellular stresses

2012 ◽  
Vol 23 (23) ◽  
pp. 4635-4646 ◽  
Author(s):  
Zengpeng Li ◽  
Jingjing Hou ◽  
Li Sun ◽  
Taoyong Wen ◽  
Liqin Wang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ubiquitin Ligase ◽  
Human Cancer ◽  
Negative Regulator ◽  
Yeast Two Hybrid ◽  
Interacting Protein ◽  
Ubiquitin E3 Ligase ◽  
Oncogene Activation ◽  
Cellular Stresses ◽  
Two Hybrid

The ARF tumor suppressor is a product of the INK4a/ARF locus, which is frequently mutated in human cancer. The expression of ARF is up-regulated in response to certain types of DNA damage, oncogene activation, and interferon stimuli. Through interaction with the p53 negative regulator MDM2, ARF controls a well-described p53/MDM2-dependent checkpoint. However, the mechanism of ARF induction is poorly understood. Using a yeast two-hybrid screen, we identify a novel ARF-interacting protein, N-Myc and STATs interactor (NMI). Previously, NMI was known to be a c-Myc–interacting protein. Here we demonstrate that through competitive binding to the ARF ubiquitin E3 ligase (ubiquitin ligase for ARF [ULF]), NMI protects ARF from ULF-mediated ubiquitin degradation. In response to cellular stresses, NMI is induced, and a fraction of NMI is translocated to the nucleus to stabilize ARF. Thus our work reveals a novel NMI-mediated, transcription-independent ARF induction pathway in response to cellular stresses.

scholarly journals Phosphorylation of Serine 18 Regulates Distinct p53 Functions in Mice

2004 ◽  
Vol 24 (3) ◽  
pp. 976-984 ◽  
Author(s):  
Hayla K. Sluss ◽  
Heather Armata ◽  
Judy Gallant ◽  
Stephen N. Jones
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Complex Formation ◽  
Ataxia Telangiectasia ◽  
P53 Protein ◽  
Growth Arrest ◽  
Embryonic Fibroblasts ◽  
Cycle Arrest ◽  
Oncogene Activation ◽  
Dependent Growth

ABSTRACT The p53 protein acts a tumor suppressor by inducing cell cycle arrest and apoptosis in response to DNA damage or oncogene activation. Recently, it has been proposed that phosphorylation of serine 15 in human p53 by ATM (mutated in ataxia telangiectasia) kinase induces p53 activity by interfering with the Mdm2-p53 complex formation and inhibiting Mdm2-mediated destabilization of p53. Serine 18 in murine p53 has been implicated in mediating an ATM- and ataxia telangiectasia-related kinase-dependent growth arrest. To explore further the physiological significance of phosphorylation of p53 on Ser18, we generated mice bearing a serine-to-alanine mutation in p53. Analysis of apoptosis in thymocytes and splenocytes following DNA damage revealed that phosphorylation of serine 18 was required for robust p53-mediated apoptosis. Surprisingly, p53Ser18 phosphorylation did not alter the proliferation rate of embryonic fibroblasts or the p53-mediated G1 arrest induced by DNA damage. In addition, endogenous basal levels and DNA damage-induced levels of p53 were not affected by p53Ser18 phosphorylation. p53Ala18 mice developed normally and were not susceptible to spontaneous tumorigenesis, and the reduced apoptotic function of p53Ala18 did not rescue the embryo-lethal phenotype of Mdm2-null mice. These results indicate that phosphorylation of the ATM target site on p53 specifically regulates p53 apoptotic function and further reveal that phosphorylation of p53 serine 18 is not required for p53-mediated tumor suppression.

Mast cell-nerve fiber interaction: Ultrastructural studies

1990 ◽  
Vol 48 (3) ◽  
pp. 428-429
Author(s):  
E.Y. Chi ◽  
M.L. Su ◽  
Y.T. Tien ◽  
W.R. Henderson
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Substance P ◽  
Nerve Fiber ◽  
Sensory Nerves ◽  
Ultrastructural Studies ◽  
Morphological Studies ◽  
Granulocyte Infiltration ◽  
Intracutaneous Injection ◽  
Recent Attention

Recent attention has been directed to the interaction of the nerve and immune systems. The neuropeptide substance P, a tachykinnin which is a neurotransmitter in the central and peripheral nervous systems produces tissue swelling, augemntation of intersitial fibrin deposition and leukocyte infiltration after intracutaneous injection. There is a direct correlation reported between the extent of mast cell degranulation at the sites of injection and the tissue swelling or granulocyte infiltration. It has previously been demonstrated that antidromic electrical stimulation of sensory nerves induces degranulation of cutaneous mast cells, cutaneous vasodilation and augmented vascular permeability. Morphological studies have documented a close anatiomical association between mast cells and nonmyelinated nerves, that contain substance P and other neuropeptides. However, the presence of mast cells within nerve fasicles has not been previously examined ultrastructurally. In this study, we examined ultrastructurally the distribution of mast cells in the nerve fiber bundles located in the muscular connective tissue of rat tongues (n=20).

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