Role of the cJun NH2-Terminal Kinase (JNK) in Cancer: A Dissertation

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dc.contributor.advisorRoger J. Davis, Ph.D.
dc.contributor.authorCellurale, Cristina Arrigo
dc.contributor.departmentProgram in Molecular Medicine
dc.date2022-08-11T08:08:42.000
dc.date.accessioned2022-08-23T16:05:05Z
dc.date.available2022-08-23T16:05:05Z
dc.date.issued2010-07-13
dc.date.submitted2010-10-22
dc.description.abstractcJun NH2-terminal kinase (JNK) is a member of the MAPK (mitogen- activated protein kinase) signaling family that responds to various extracellular stimuli, such as stress, growth factors, cytokines, or UV radiation. JNK activation can lead to cellular responses including gene expression, growth, survival, and apoptosis. JNK has been implicated in normal developmental processes, including tissue morphogenesis, as well as pathological processes, such as cellular transformation and cancer. JNK exists in three isoforms, and knockout mice have been generated for each isoform; the ubiquitously expressed Jnk1 and Jnk2 have been studied independently, however, the two isoforms are partially functionally redundant. Jnk1-/- Jnk2-/-mice are nonviable, therefore studies of compound JNK-deficiency have been limited to mouse embryonic fibroblasts (MEF). Understanding the role of JNK in epithelial cells is now possible with the creation of conditional JNK knockout animals. I sought to elucidate the role of JNK in cellular transformation, cancer, and normal development. I employed both in vitro and in vivo approaches. First, I evaluated the role of JNK in cellular transformation using p53-/- Jnk1-/- Jnk2-/- MEF transduced with oncogenic Ras. To extend this study, I examined JNK-deficiency in a Kras-induced model of lung tumorigenesis. Second, I investigated JNK1- and JNK2-deficiency in a p53-mediated model of mammary tumorigenesis. Finally, I examined the role of JNK in mouse mammary gland development by establishing JNK-deficient primary mouse mammary epithelial cells and evaluating JNK-deficient mammary gland transplants. Taken together, this work provides evidence of context-dependent roles for JNK in both normal and pathological cell biology.
dc.description.thesisprogramMD/PhD
dc.identifier.contextkey1614291
dc.identifier.doi10.13028/dqzg-n223
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/478
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1480&context=gsbs_diss&unstamped=1
dc.identifier.submissionpathgsbs_diss/478
dc.identifier.urihttps://hdl.handle.net/20.500.14038/31810
dc.language.isoen_US
dc.legacy.embargo2011-08-02T00:00:00-07:00
dc.publisherUniversity of Massachusetts Medical School
dc.rightsCopyright is held by the author, with all rights reserved.
dc.subjectJNK Mitogen-Activated Protein Kinases
dc.subjectNeoplasms
dc.subjectCell Transformation
dc.subjectNeoplastic
dc.subjectMice
dc.subjectKnockout
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectCell and Developmental Biology
dc.subjectCells
dc.subjectEnzymes and Coenzymes
dc.subjectMolecular Genetics
dc.subjectNeoplasms
dc.titleRole of the cJun NH2-Terminal Kinase (JNK) in Cancer: A Dissertation
dc.typeDoctoral Dissertation
dspace.entity.typePublication
html.description.abstract<p>cJun NH<sub>2</sub>-terminal kinase (JNK) is a member of the MAPK (mitogen- activated protein kinase) signaling family that responds to various extracellular stimuli, such as stress, growth factors, cytokines, or UV radiation. JNK activation can lead to cellular responses including gene expression, growth, survival, and apoptosis. JNK has been implicated in normal developmental processes, including tissue morphogenesis, as well as pathological processes, such as cellular transformation and cancer. JNK exists in three isoforms, and knockout mice have been generated for each isoform; the ubiquitously expressed <em>Jnk1</em> and <em>Jnk2</em> have been studied independently, however, the two isoforms are partially functionally redundant. <em>Jnk1<sup>-/-</sup></em> <em>Jnk2<sup>-/-</sup></em>mice are nonviable, therefore studies of compound JNK-deficiency have been limited to mouse embryonic fibroblasts (MEF). Understanding the role of JNK in epithelial cells is now possible with the creation of conditional JNK knockout animals.</p> <p>I sought to elucidate the role of JNK in cellular transformation, cancer, and normal development. I employed both <em>in vitro</em> and <em>in vivo</em> approaches. First, I evaluated the role of JNK in cellular transformation using <em>p53<sup>-/-</sup></em> <em>Jnk1<sup>-/-</sup></em> <em>Jnk2<sup>-/-</sup></em> MEF transduced with oncogenic Ras. To extend this study, I examined JNK-deficiency in a Kras-induced model of lung tumorigenesis. Second, I investigated JNK1- and JNK2-deficiency in a p53-mediated model of mammary tumorigenesis. Finally, I examined the role of JNK in mouse mammary gland development by establishing JNK-deficient primary mouse mammary epithelial cells and evaluating JNK-deficient mammary gland transplants. Taken together, this work provides evidence of context-dependent roles for JNK in both normal and pathological cell biology.</p>
refterms.dateFOA2022-08-30T04:39:22Z
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