Abdolrahman S. Nateri

Jun N-terminal kinases (JNKs) are essential for neuronal microtubule assembly and apoptosis. Phosphorylation of the activating protein 1 (AP1) transcription factor c-Jun, at multiple sites within its transactivation domain, is required for JNK-induced neurotoxicity. We report that in neurons the stability of c-Jun is regulated by the E3 ligase SCF(Fbw7), which ubiquitinates phosphorylated c-Jun and facilitates c-Jun degradation. Fbw7 depletion resulted in accumulation of phosphorylated c-Jun, stimulation of AP1 activity, and neuronal apoptosis. SCF(Fbw7) therefore antagonizes the apoptotic c-Jun-dependent effector arm of JNK signaling, allowing neurons to tolerate potentially neurotoxic JNK activity.

The Fbxw7 (F-box/WD repeat-containing protein 7; also called CDC4, Sel10, Ago, and Fbw7) component of the SCF (Skp1/Cullin/F-box protein) E3 ubiquitin ligase complex acts as a tumor suppressor in several tissues and targets multiple transcriptional activators and protooncogenes for ubiquitin-mediated degradation. To understand Fbxw7 function in the murine intestine, in this study, we specifically deleted Fbxw7 in the murine gut using Villin-Cre (Fbxw7(ΔG)). In wild-type mice, loss of Fbxw7 in the gut altered homeostasis of the intestinal epithelium, resulted in elevated Notch and c-Jun expression, and induced development of adenomas at 9-10 mo of age. In the context of APC (adenomatous polyposis coli) deficiency (Apc(Min/+) mice), loss of Fbxw7 accelerated intestinal tumorigenesis and death and promoted accumulation of β-catenin in adenomas at late but not early time points. At early time points, Fbxw7 mutant tumors showed accumulation of the DEK protooncogene. DEK expression promoted cell division and altered splicing of tropomyosin (TPM) RNA, which may also influence cell proliferation. DEK accumulation and altered TPM RNA splicing were also detected in FBXW7 mutant human colorectal tumor tissues. Given their reduced lifespan and increased incidence of intestinal tumors, Apc(Min/+)Fbxw7(ΔG) mice may be used for testing carcinogenicity and drug screening.

Carcinomas are complex heterocellular systems containing epithelial cancer cells, stromal fibroblasts, and multiple immune cell-types. Cell-cell communication between these tumor microenvironments (TME) and cells drives cancer progression and influences response to existing therapies. In order to provide better treatments for patients, we must understand how various cell-types collaborate within the TME to drive cancer and consider the multiple signals present between and within different cancer types. To investigate how tissues function, we need a model to measure both how signals are transferred between cells and how that information is processed within cells. The interplay of collaboration between different cell-types requires cell-cell communication. This article aims to review the current in vitro and in vivo mono-cellular and multi-cellular cultures models of colorectal cancer (CRC), and to explore how they can be used for single-cell multi-omics approaches for isolating multiple types of molecules from a single-cell required for cell-cell communication to distinguish cancer cells from normal cells. Integrating the existing single-cell signaling measurements and models, and through understanding the cell identity and how different cell types communicate, will help predict drug sensitivities in tumor cells and between- and within-patients responses.