Date

7-13-2010

UMMS Affiliation

Graduate School of Biomedical Sciences, MD/PhD Program

Document Type

Dissertation, Doctoral

Subjects

JNK Mitogen-Activated Protein Kinases; Neoplasms; Cell Transformation, Neoplastic; Mice, Knockout; Dissertations, UMMS

Disciplines

Cell and Developmental Biology | Life Sciences | Medicine and Health Sciences | Molecular genetics

Abstract

cJun 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.