Estrogen Regulates JNK1 Genomic Localization to Control Gene Expression and Cell Growth in Breast Cancer Cells
ABSTRACT Steroid hormone and MAPK signaling pathways functionally intersect, but the molecular mechanisms of this cross talk are unclear. Here, we demonstrate a functional convergence of the estrogen and c-Jun N-terminal kinase 1 (JNK1) signaling pathways at the genomic level in breast cancer cells. We find that JNK1 binds to many promoters across the genome. Although most of the JNK1-binding sites are constitutive, a subset is estrogen regulated (either induced on inhibited). At the estrogen-induced sites, estrogen receptor (ER)α is required for the binding of JNK1 by promoting its recruitment to estrogen response elements or other classes of DNA elements through a tethering mechanism, which in some cases involves activating protein-1. At estrogen-regulated promoters, JNK1 functions as a transcriptional coregulator of ERα in a manner that is dependent on its kinase activity. The convergence of ERα and JNK1 at target gene promoters regulates estrogen-dependent gene expression outcomes, as well as downstream estrogen-dependent cell growth responses. Analysis of existing gene expression profiles from breast cancer biopsies suggests a role for functional interplay between ERα and JNK1 in the progression and clinical outcome of breast cancers.
Article: Chromatin-tethered MAPKs[Show abstract] [Hide abstract]
ABSTRACT: Mitogen-activated protein kinases (MAPKs) are a family of protein kinases that are essential nodes in many cellular regulatory circuits including those that take place on DNA. Most members of the four MAPK subgroups that exist in canonical three kinase cascades-extracellular signal-regulated kinases 1 and 2 (ERK1/2), ERK5, c-Jun N-terminal kinases (JNK1-3), and p38 (α, β, γ, and δ) families-have been shown to perform regulatory functions on chromatin. This review offers a brief update on the variety of processes that involve MAPKs and available mechanisms garnered in the last two years.Current opinion in cell biology 02/2013; 25(2). DOI:10.1016/j.ceb.2013.01.002 · 8.47 Impact Factor
Article: Network motifs in JNK signaling[Show abstract] [Hide abstract]
ABSTRACT: Multiple growth factors and extracellular signals can lead to activation of the c-Jun amino N-terminal protein kinase (JNK) pathway. Activation of JNK can in turn lead to a multitude of downstream changes in phosphorylation and transcriptional activation within the cell. Mapping the upstream and downstream connectivity within the JNK network reveals an enrichment of bi-fan and feed-forward network motifs formed immediately upstream and downstream of JNK. In addition, negative feedback loops also exist through transcriptional activation of phosphatases that target the JNK pathway. The combinations of these motifs allow flexibility and tunability in signal integration and processing within the JNK network and may confer the wide range of biological responses that can be regulated by JNK activation. In this review, we highlight the pathways and motifs leading to JNK activation and its downstream signaling as well as the complexity in isoforms within this network.Genes & cancer 09/2013; 4(9-10):409-413. DOI:10.1177/1947601913507577
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ABSTRACT: The c-Jun N-terminal kinases (JNKs) play an important role in many physiological processes induced by numerous stress signals. Each JNK protein appears to have a distinct function in cancer, diabetes, or Parkinson's disease. Herein, we found that licochalcone A, a major phenolic constituent isolated from licorice root, suppressed JNK1 activity, but had little effect on JNK2 in vitro activity. Although licochalcone A binds with JIP1 competitively with either JNK1 or JNK2, a computer simulation model showed that after licochalcone A binding, the ATP-binding cleft of JNK1 was distorted more substantially than that of JNK2. This could reduce the affinity of JNK1 more than JNK2 for ATP binding. Furthermore, licochalcone A inhibited JNK1-mediated, but not JNK2-mediated, c-Jun phosphorylation in both ex vivo and in vitro systems. We also observed that in colon and pancreatic cancer cell lines, JNK1 is highly expressed compared with normal cell lines. In cancer cell lines, treatment with licochalcone A or knocking down JNK1 expression suppressed colon and pancreatic cancer cell proliferation and colony formation. The inhibition resulted in G1 phase arrest and apoptosis. Moreover, an in vivo xenograft mouse study showed that licochalcone A treatment effectively suppressed the growth of HCT116 xenografts, without affecting the body weight of mice. These results demonstrate that licochalcone A is a selective JNK1 inhibitor. Therefore, we suggest that because of JNK1's critical role in colon cancer and pancreatic carcinogenesis, licochalcone A might have preventive or therapeutic potential against these devastating diseases.Cancer Prevention Research 11/2013; 7(1). DOI:10.1158/1940-6207.CAPR-13-0117 · 4.44 Impact Factor