ENDOCYTIC PATHWAYS AND INTRACELLULAR PROCESSING IN THE MECHANISMS OF ACTION OF INSULIN AND EPIDERMAL GROWTH FACTOR.

Persistent Link:
http://hdl.handle.net/10150/185127
Title:
ENDOCYTIC PATHWAYS AND INTRACELLULAR PROCESSING IN THE MECHANISMS OF ACTION OF INSULIN AND EPIDERMAL GROWTH FACTOR.
Author:
MISKIMINS, WILSON KEITH.
Issue Date:
1982
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
The mechanism of action of insulin and epidermal growth factor was studied by genetic and biochemical means. Particular emphasis was placed on the ability of these factors to induce DNA synthesis and the relationship of endocytosis to that ability. Insulin was crosslinked to the active fragment A of diphtheria toxin. This conjugate specifically killed cultured mouse cells through an insulin receptor-mediated process. The conjugate was used to select genetic variants resistant to its cytotoxic effect. Six resistant variants were isolated, 2 of which retained very low insulin receptor activity. When these two variants were further analyzed both displayed altered cell shape and growth properties. The CI-3 variant also was shown to have a deficient lysosomal system and failed to efficiently degrade epidermal growth factor. This variant was, however, fully responsive to the mitogenic action of EGF. This suggested that lysosomal processing is unimportant in the production of a mitogenic stimulus by EGF. EGF was found to be endocytosed by fibroblasts through 2 separate pathways. One pathway involves an unidentified organelle and correlated with increased degradation of the ligand. The other pathway involves a Golgi-like component and is correlated with a lack of degradation and uptake into a dense, non-lysosomal organelle. Uptake of EGF into this non-lysosomal component, which we named mitosomes, correlated with the ability of EGF to induce DNA synthesis. From these results, a model was constructed for the coupling of endocytosis, uptake into mitosomes and the stimulation of DNA synthesis.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Peptide hormones -- Receptors.; Endocytosis.; DNA -- Synthesis.; Insulin -- Receptors.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Cellular and Developmental Biology; Graduate College
Degree Grantor:
University of Arizona

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleENDOCYTIC PATHWAYS AND INTRACELLULAR PROCESSING IN THE MECHANISMS OF ACTION OF INSULIN AND EPIDERMAL GROWTH FACTOR.en_US
dc.creatorMISKIMINS, WILSON KEITH.en_US
dc.contributor.authorMISKIMINS, WILSON KEITH.en_US
dc.date.issued1982en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractThe mechanism of action of insulin and epidermal growth factor was studied by genetic and biochemical means. Particular emphasis was placed on the ability of these factors to induce DNA synthesis and the relationship of endocytosis to that ability. Insulin was crosslinked to the active fragment A of diphtheria toxin. This conjugate specifically killed cultured mouse cells through an insulin receptor-mediated process. The conjugate was used to select genetic variants resistant to its cytotoxic effect. Six resistant variants were isolated, 2 of which retained very low insulin receptor activity. When these two variants were further analyzed both displayed altered cell shape and growth properties. The CI-3 variant also was shown to have a deficient lysosomal system and failed to efficiently degrade epidermal growth factor. This variant was, however, fully responsive to the mitogenic action of EGF. This suggested that lysosomal processing is unimportant in the production of a mitogenic stimulus by EGF. EGF was found to be endocytosed by fibroblasts through 2 separate pathways. One pathway involves an unidentified organelle and correlated with increased degradation of the ligand. The other pathway involves a Golgi-like component and is correlated with a lack of degradation and uptake into a dense, non-lysosomal organelle. Uptake of EGF into this non-lysosomal component, which we named mitosomes, correlated with the ability of EGF to induce DNA synthesis. From these results, a model was constructed for the coupling of endocytosis, uptake into mitosomes and the stimulation of DNA synthesis.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectPeptide hormones -- Receptors.en_US
dc.subjectEndocytosis.en_US
dc.subjectDNA -- Synthesis.en_US
dc.subjectInsulin -- Receptors.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineCellular and Developmental Biologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.identifier.proquest8305987en_US
dc.identifier.oclc686766441en_US
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