Browsing by keyword "AP1"

Now showing items 1-3 of 3

    • Suppression of p53-dependent senescence by the JNK signal transduction pathway
      Das, Madhumita; Jiang, Feng; Sluss, Hayla Karen; Zhang, Chao; Shokat, Kevan M.; Flavell, Richard A.; Davis, Roger J. (2007-10-02)
      The JNK signaling pathway is implicated in the regulation of the AP1 transcription factor and cell proliferation. Here, we examine the role of JNK by using conditional and chemical genetic alleles of the ubiquitously expressed murine genes that encode the isoforms JNK1 and JNK2. Our analysis demonstrates that JNK is not essential for proliferation. However, JNK is required for expression of the cJun and JunD components of the AP1 transcription factor, and JNK-deficient cells exhibit early p53-dependent senescence. These data demonstrate that JNK can act as a negative regulator of the p53 tumor suppressor.

    • Tead and AP1 Coordinate Transcription and Motility
      Liu, Xiangfan; Li, Huapeng; Rajurkar, Mihir S.; Li, Qi; Cotton, Jennifer L.; Ou, Jianhong; Zhu, Lihua J.; Goel, Hira L.; Mercurio, Arthur M.; Park, Joo-Seop; et al. (2016-02-09)
      The Tead family transcription factors are the major intracellular mediators of the Hippo-Yap pathway. Despite the importance of Hippo signaling in tumorigenesis, Tead-dependent downstream oncogenic programs and target genes in cancer cells remain poorly understood. Here, we characterize Tead4-mediated transcriptional networks in a diverse range of cancer cells, including neuroblastoma, colorectal, lung, and endometrial carcinomas. By intersecting genome-wide chromatin occupancy analyses of Tead4, JunD, and Fra1/2, we find that Tead4 cooperates with AP1 transcription factors to coordinate target gene transcription. We find that Tead-AP1 interaction is JNK independent but engages the SRC1-3 co-activators to promote downstream transcription. Furthermore, we show that Tead-AP1 cooperation regulates the activity of the Dock-Rac/CDC42 module and drives the expression of a unique core set of target genes, thereby directing cell migration and invasion. Together, our data unveil a critical regulatory mechanism underlying Tead- and AP1-controlled transcriptional and functional outputs in cancer cells.

    • The cJUN NH2-terminal kinase pathway in mammary gland biology and carcinogenesis
      Girnius, Nomeda A. (2018-03-08)
      The cJUN NH2-terminal kinase (JNK) pathway responds to environmental stresses and participates in many cellular processes, including cell death, survival, proliferation, migration, and genome maintenance. Importantly, genes that encode components of the JNK signaling pathway are frequently mutated in human breast cancer, but the functional consequence of these mutations in mammary carcinogenesis is unclear. Anoikis – suspension-induced apoptosis – has been implicated in oncogenic transformation and tumor cell metastasis. Anoikis also contributes to lumen formation during mammary gland development and epithelial cell clearance during post-lactational involution. JNK is known to contribute to certain forms of cell death, but the role of JNK during anoikis was unclear. I examined the requirement of JNK in anoikis and discovered that JNK promotes cell death by transcriptional and post-translational regulation of pro-apoptotic BH3-only proteins. This conclusion suggested that JNK signaling may contribute to mammary gland remodeling during involution. Indeed, JNK deficiency in mammary epithelial cells disrupted the remodeling program of gene expression and delayed involution. Finally, I sought to understand the importance of JNK in mammary carcinogenesis. I found that JNK loss in the mammary epithelium was sufficient for genomic instability and tumor formation. Moreover, JNK loss in a model of breast cancer resulted in significantly accelerated tumor development. Collectively, these studies advance our understanding of the JNK pathway and breast biology, and provide insight that informs the design of therapeutic approaches that target the JNK signal transduction pathway.