Cancer cells can adapt and survive under low nutrient conditions, but underlying mechanisms remain poorly explored. We demonstrate here that glucose maintains a functional complex between the co-chaperone URI, PP1γ, and OGT, the enzyme catalyzing O-GlcNAcylation. Glucose deprivation induces the activation of PKA, which phosphorylates URI at Ser-371, resulting in PP1γ release and URI-mediated OGT inhibition. Low OGT activity reduces O-GlcNAcylation and promotes c-MYC degradation to maintain cell survival. In the presence of glucose, PP1γ-bound URI increases OGT and c-MYC levels. Accordingly, mice expressing non-phosphorylatable URI (S371A) in hepatocytes exhibit high OGT activity and c-MYC stabilization, accelerating liver tumorigenesis in agreement with c-MYC oncogenic functions. Our work uncovers that URI-regulated OGT confers c-MYC-dependent survival functions in response to glucose fluctuations.

Ras homolog enriched in brain (Rheb) is critical for mechanistic target of rapamycin complex 1 (mTORC1) activation in response to growth factors and amino acids (AAs). Whereas growth factors inhibit the tuberous sclerosis complex (TSC1-TSC2), a negative Rheb regulator, the role of AAs in Rheb activation remains unknown. Here, we identify microspherule protein 1 (MCRS1) as the essential link between Rheb and mTORC1 activation. MCRS1, in an AA-dependent manner, maintains Rheb at lysosome surfaces, connecting Rheb to mTORC1. MCRS1 suppression in human cancer cells using small interference RNA or mouse embryonic fibroblasts using an inducible-Cre/Lox system reduces mTORC1 activity. MCRS1 depletion promotes Rheb/TSC2 interaction, rendering Rheb inactive and delocalizing it from lysosomes to recycling endocytic vesicles, leading to mTORC1 inactivation. These findings have important implications for signaling mechanisms in various pathologies, including diabetes mellitus and cancer.

IntroductionAnaplastic large cell lymphoma (ALCL) is a T/null-cell neoplasm characterized by the expression of a hybrid protein comprising an N-terminal partner protein fused to the cytoplasmic portion of the anaplastic lymphoma kinase (ALK) tyrosine kinase. The fulllength ALK protein belongs to the family of receptor tyrosine kinases and is highly conserved across species. 1 In approximately 80% of ALK-positive lymphomas, the hybrid kinase is the NPM-ALK fusion protein that is encoded by the nucleophosmin (NPM)-ALK fusion gene resulting from the (2;5)(p23;q35) chromosomal translocation. [2][3][4] Other translocations have been described involving the ALK gene and other partners, including TFG, 5 CLTC, 6 ATIC, 6,7 and TPM3. 8 In NPM-ALK, as well as in variant fusion proteins, the N-terminal partner protein is widely expressed in normal cells due to ubiquitous transcription of the corresponding promoter. Thus, cells that do not normally express the full-length ALK receptor because of its restricted tissue distribution 4,9 display, if they contain an X-ALK translocation, anomalous transcription of the ALK chimeric mRNA and aberrant expression of the encoded fusion protein. In addition, the N-terminal partner protein (NPM or other variants) contains an oligomerization motif that enables the fusion protein to form homodimers as well as heterodimers with the full-length partner (Bischof et al 10 and review in Pulford et al 1 ). Oligomerization of the fusion protein results in the constitutive activation of the ALK tyrosine kinase catalytic domain contained in its carboxy-terminal part. This, in turn, leads to abnormal activation of multiple downstream signaling cascades that are responsible for the neoplastic transformation of cells, involving, among others, phospholipase C-gamma (PLC␥), 11 phosphoinositide 3-kinase (PI3K), 12 13,15 as well as Src kinases. 16 Several model systems have been established to study the oncogenic mechanisms used by ALK fusion proteins, including transgenic mice, which develop lymphoma when NPM-ALK expression is directed to lymphocytes, 17,18 and cultured cells which acquire transformed properties when they express ALK fusion . A recent analysis of NPM-ALK-associated proteins in the t(2;5)-positive line Karpas 299 led to the identification of a number of proteins and highlighted the complexity of the molecular mechanisms underlying NPM-ALK oncogenicity. 20 In this study, we characterized AUF1/hnRNPD as a new partner of NPM-ALK. AUF1 belongs to the family of AU-binding proteins (AU-BPs) that regulate the cellular half-lives of many mRNAs by directly interacting with an AU-rich element (ARE) located in their 3Ј untranslated region. [21][22][23] Although AREs are found in mRNAs coding for a wide range of proteins, 24 many ARE-containing mRNAs are transcribed from early response genes (ERGs) encoding proto-oncogene products (such as c-Myc), cytokines, cyclins (such as cyclins D1, A2, and B1) and growth factors involved in the control of cell growth and proliferation. Here, we demonstrate that...

Dietary habits that can induce inflammatory bowel disease (IBD) are major colorectal cancer (CRC) risk factors, but mechanisms linking nutrients, IBD, and CRC are unknown. Using human data and mouse models, we show that mTORC1 inactivation-induced chromosomal instability impairs intestinal crypt proliferation and regeneration, CDK4/6 dependently. This triggers interleukin (IL)-6-associated reparative inflammation, inducing crypt hyper-proliferation, wound healing, and CRC. Blocking IL-6 signaling or reactivating mTORC1 reduces inflammation-induced CRC, so mTORC1 activation suppresses tumorigenesis in IBD. Conversely, mTORC1 inactivation is beneficial in APC loss-dependent CRC. Thus, IL-6 blockers or protein-rich-diet-linked mTORC1 activation may prevent IBD-associated CRC. However, abolishing mTORC1 can mitigate CRC in predisposed patients with APC mutations. Our work reveals mTORC1 oncogenic and tumor-suppressive roles in intestinal epithelium and avenues to optimized and personalized therapeutic regimens for CRC.

The CCAAT/enhancer-binding protein b (C/EBPb) plays a major role in the pathogenesis of anaplastic large cell lymphomas (ALCL) that express the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) tyrosine kinase (ALK þ ). Although ALK-mediated C/EBPb transcriptional activation has been reported, C/EBPb mRNA possesses U-and AU-rich domains in its 3 0 -untranslated region (3 0 -UTR) that might be privileged targets for posttranscriptional control in ALK þ ALCLs. The purpose of this study was to explore this possibility. By using human ALCL-derived cells and a murine model of ALK-transformed cells, we show that the AU-binding protein HuR binds to the 3 0

Abscission is the last step of cytokinesis, allowing the physical separation of daughter cells at the end of cell division. It has been considered a cell autonomous process, yet Jungas et al. report that Ephrin/Eph signaling controls the completion of abscission.

Balancing self-renewal with differentiation is crucial for neural stem cells (NSC) functions to ensure tissue development and homeostasis. Over the last years, multiple studies have highlighted the coupling of either metabolic or epigenetic reprogramming to NSC fate decisions. Metabolites are essential as they provide the energy and building blocks for proper cell function. Moreover, metabolites can also function as substrates and/or cofactors for epigenetic modifiers. It is becoming more evident that metabolic alterations and epigenetics rewiring are highly intertwined; however, their relation regarding determining NSC fate is not well understood. In this review, we summarize the major metabolic pathways and epigenetic modifications that play a role in NSC. We then focus on the notion that nutrients availability can function as a switch to modify the epigenetic machinery and drive NSC sequential differentiation during embryonic neurogenesis.

Metabolic pathways, once seen as a mere consequence of cell states, have emerged as active players in dictating different cellular events such as proliferation, self-renewal, and differentiation. Several studies have reported a role for folate-dependent one-carbon (1C) metabolism in stem cells; however, its exact mode of action and how it interacts with other cues are largely unknown. Here, we report a link between the Eph:ephrin cell-cell communication pathway and 1C metabolism in controlling neural stem cell differentiation. Transcriptional and functional analyses following ephrin stimulation revealed alterations in folate metabolism-related genes and enzymatic activity. In vitro and in vivo data indicate that Eph-B forward signaling alters the methylation state of H3K4 by regulating 1C metabolism and locks neural stem cell in a differentiation-ready state. Our study highlights a functional link between cell-cell communication, metabolism, and epigenomic remodeling in the control of stem cell self-renewal.