Fermenting a place in history: The first outbreak of Escherichia coli O157 associated with kimchi in Canada.

A Canadian outbreak investigation was initiated in January 2022 after a cluster of cases of Shiga-toxin-producing Escherichia coli (STEC) O157 was identified through whole genome sequencing (WGS). Exposure information was collected through case interviews. Traceback investigations were conducted, and samples from case homes, retail, and the manufacturer were tested for STEC O157. Fourteen cases were identified in two provinces in Western Canada, with isolates related by 0-5 whole genome multi-locus sequence typing allele differences. Symptom onset dates ranged from 11 December 2021 to 7 January 2022. The median age of cases was 29.5 (range 0-61); 64% were female. No hospitalisations or deaths were reported. Of 11 cases with information available on fermented vegetable exposures, 91% (10/11) reported consuming Kimchi Brand A during their exposure period. The traceback investigation identified Manufacturer A in Western Canada as the producer. One open and one closed sample of Kimchi Brand A tested positive for STEC O157, with isolates considered genetically related by WGS to the outbreak strain. Napa cabbage within the kimchi product was hypothesised as the most likely source of contamination. This paper summarises the investigation into this STEC O157 outbreak associated with kimchi, the first reported outside of East Asia.

Regulatory Role of microRNAs Targeting the Transcription Co-Factor ZNF521 in Normal Tissues and Cancers.

Powerful bioinformatics tools have provided a wealth of novel miRNA-transcription factor networks crucial in controlling gene regulation. In this review, we focus on the biological functions of miRNAs targeting ZNF521, explaining the molecular mechanisms by which the dysregulation of this axis contributes to malignancy. ZNF521 is a stem cell-associated co-transcription factor implicated in the regulation of hematopoietic, neural, and mesenchymal stem cells. The aberrant expression of ZNF521 transcripts, frequently associated with miRNA deregulation, has been detected in several tumors including pancreatic, hepatocellular, gastric, bladder transitional cell carcinomas as well as in breast and ovarian cancers. miRNA expression profiling tools are currently identifying a multitude of miRNAs, involved together with oncogenes and TFs in the regulation of oncogenesis, including ZNF521, which may be candidates for diagnostic and prognostic biomarkers of cancer.

ZNF521 Enhances MLL-AF9-Dependent Hematopoietic Stem Cell Transformation in Acute Myeloid Leukemias by Altering the Gene Expression Landscape.

Leukemias derived from the MLL-AF9 rearrangement rely on dysfunctional transcriptional networks. ZNF521, a transcription co-factor implicated in the control of hematopoiesis, has been proposed to sustain leukemic transformation in collaboration with other oncogenes. Here, we demonstrate that ZNF521 mRNA levels correlate with specific genetic aberrations: in particular, the highest expression is observed in AMLs bearing MLL rearrangements, while the lowest is detected in AMLs with FLT3-ITD, NPM1, or CEBPα double mutations. In cord blood-derived CD34+ cells, enforced expression of ZNF521 provides a significant proliferative advantage and enhances MLL-AF9 effects on the induction of proliferation and the expansion of leukemic progenitor cells. Transcriptome analysis of primary CD34+ cultures displayed subsets of genes up-regulated by MLL-AF9 or ZNF521 single transgene overexpression as well as in MLL-AF9/ZNF521 combinations, at either the early or late time points of an in vitro leukemogenesis model. The silencing of ZNF521 in the MLL-AF9 + THP-1 cell line coherently results in an impairment of growth and clonogenicity, recapitulating the effects observed in primary cells. Taken together, these results underscore a role for ZNF521 in sustaining the self-renewal of the immature AML compartment, most likely through the perturbation of the gene expression landscape, which ultimately favors the expansion of MLL-AF9-transformed leukemic clones.

Lipid Droplet Biosynthesis Impairment through DGAT2 Inhibition Sensitizes MCF7 Breast Cancer Cells to Radiation.

Breast cancer is the most frequent cancer in women worldwide and late diagnosis often adversely affects the prognosis of the disease. Radiotherapy is commonly used to treat breast cancer, reducing the risk of recurrence after surgery. However, the eradication of radioresistant cancer cells, including cancer stem cells, remains the main challenge of radiotherapy. Recently, lipid droplets (LDs) have been proposed as functional markers of cancer stem cells, also being involved in increased cell tumorigenicity. LD biogenesis is a multistep process requiring various enzymes, including Diacylglycerol acyltransferase 2 (DGAT2). In this context, we evaluated the effect of PF-06424439, a selective DGAT2 inhibitor, on MCF7 breast cancer cells exposed to X-rays. Our results demonstrated that 72 h of PF-06424439 treatment reduced LD content and inhibited cell migration, without affecting cell proliferation. Interestingly, PF-06424439 pre-treatment followed by radiation was able to enhance radiosensitivity of MCF7 cells. In addition, the combined treatment negatively interfered with lipid metabolism-related genes, as well as with EMT gene expression, and modulated the expression of typical markers associated with the CSC-like phenotype. These findings suggest that PF-06424439 pre-treatment coupled to X-ray exposure might potentiate breast cancer cell radiosensitivity and potentially improve the radiotherapy effectiveness.

Nasal Polyposis: Insights in Epithelial-Mesenchymal Transition and Differentiation of Polyp Mesenchymal Stem Cells.

Chronic rhinosinusitis is a common inflammatory disease of paranasal sinuses, which causes rhinorrhea, nasal congestion, and hyposmia. The genetic predisposition or the exposure to irritants can sustain the inflammatory response and the development of nasal polyposis. Nasal polyps are benign and teardrop-shaped growths that project in the nasal cavities, and originate from the ethmoid sinuses. This inflammatory process is associated with high expression of IL-4, IL-5 and IL-13 and IgE. Antibodies targeting these cytokines or receptors represent a therapeutic strategy in the treatment of nasal polyposis in combination with corticosteroids. The molecular pathogenesis of nasal polyps in chronic rhinosinusitis (CRS) patients is associated with remodeling transition, a process in which epithelial cells lose their typical phenotype, acquiring a mesenchymal-like aspect. TGFß/SMAD, ERK, and Wnt/ß-catenin pathways are altered during the nasal tissue remodeling. miRNA and inhibitor molecules targeting these signaling pathways are able to interfere with the process; which could lead to alternative therapies. Nasal polyps are an alternative source of mesenchymal stem cells, which can be isolated from surgical biopsies. A molecular understanding of the biology of PO-MSCs will contribute to the delineating inflammatory process underlying the development of nasal polyps.

Deficit in Adipose Differentiation in Mesenchymal Stem Cells Derived from Chronic Rhinosinusitis Nasal Polyps Compared to Nasal Mucosal Tissue.

Chronic rhinosinusitis of the nasal mucosa is an inflammatory disease of paranasal sinuses, which causes rhinorrhea, nasal congestion, and hyposmia, and in some cases, it can result in the development of nasal polyposis. Nasal polyps are benign lobular-shaped growths that project in the nasal cavities; they originate from inflammation in the paranasal mucous membrane and are associated with a high expression of interleukins (IL)-4, IL-5, IL-13, and IgE. Polyps derive from the epithelial-mesenchymal transition of the nasal epithelium resulting in a nasal tissue remodeling. Nasal polyps from three patients with chronic rhinosinusitis as well as control non-polyp nasal mucosa were used to isolate and cultivate mesenchymal stem cells characterized as CD73+, CD90+, CD105+/CD14-, CD34-, and CD45-. Mesenchymal stem cells (MSCs) cultures were induced to differentiate toward adipocytes, where lipid droplets and adipocyte genes PPARγ2, ADIPO-Q, and FABP4 were observed in control non-polyp nasal mucosa-derived mesenchymal cells but were scarcely present in the cultures derived from the nasal polyps, where apoptosis was evident. The modulation of the response to adipogenic stimulus in polyps represents a change in the molecular response that controls the cascade required for differentiation as well as possible means to specifically target these cells, sparing the normal mucosa of the nasal sinuses.

ZNF521 Represses Osteoblastic Differentiation in Human Adipose-Derived Stem Cells.

Human adipose-derived stem cells (hADSCs) are multipotent mesenchymal cells that can differentiate into adipocytes, chondrocytes, and osteocytes. During osteoblastogenesis, the osteoprogenitor cells differentiate into mature osteoblasts and synthesize bone matrix components. Zinc finger protein 521 (ZNF521/Zfp521) is a transcription co-factor implicated in the regulation of hematopoietic, neural, and mesenchymal stem cells, where it has been shown to inhibit adipogenic differentiation. The present study is aimed at determining the effects of ZNF521 on the osteoblastic differentiation of hADSCs to clarify whether it can influence their osteogenic commitment. The enforced expression or silencing of ZNF521 in hADSCs was achieved by lentiviral vector transduction. Cells were cultured in a commercial osteogenic medium for up to 20 days. The ZNF521 enforced expression significantly reduced osteoblast development as assessed by the morphological and molecular criteria, resulting in reduced levels of collagen I, alkaline phosphatase, osterix, osteopontin, and calcium deposits. Conversely, ZNF521 silencing, in response to osteoblastic stimuli, induced a significant increase in early molecular markers of osteogenesis and, at later stages, a remarkable enhancement of matrix mineralization. Together with our previous findings, these results show that ZNF521 inhibits both adipocytic and osteoblastic maturation in hADSCs and suggest that its expression may contribute to maintaining the immature properties of hADSCs.

Turning Stem Cells Bad: Generation of Clinically Relevant Models of Human Acute Myeloid Leukemia through Gene Delivery- or Genome Editing-Based Approaches.

Acute myeloid leukemia (AML), the most common acute leukemia in the adult, is believed to arise as a consequence of multiple molecular events that confer on primitive hematopoietic progenitors unlimited self-renewal potential and cause defective differentiation. A number of genetic aberrations, among which a variety of gene fusions, have been implicated in the development of a transformed phenotype through the generation of dysfunctional molecules that disrupt key regulatory mechanisms controlling survival, proliferation, and differentiation in normal stem and progenitor cells. Such genetic aberrations can be recreated experimentally to a large extent, to render normal hematopoietic stem cells "bad", analogous to the leukemic stem cells. Here, we wish to provide a brief outline of the complementary experimental approaches, largely based on gene delivery and more recently on gene editing, employed over the last two decades to gain insights into the molecular mechanisms underlying AML development and progression and on the prospects that their applications offer for the discovery and validation of innovative therapies.

Ferritin Heavy Subunit Silencing Blocks the Erythroid Commitment of K562 Cells via miR-150 up-Regulation and GATA-1 Repression.

Erythroid differentiation is a complex and multistep process during which an adequate supply of iron for hemoglobinization is required. The role of ferritin heavy subunit, in this process, has been mainly attributed to its capacity to maintain iron in a non-toxic form. We propose a new role for ferritin heavy subunit (FHC) in controlling the erythroid commitment of K562 erythro-myeloid cells. FHC knockdown induces a change in the balance of GATA transcription factors and significantly reduces the expression of a repertoire of erythroid-specific genes, including α- and γ-globins, as well as CD71 and CD235a surface markers, in the absence of differentiation stimuli. These molecular changes are also reflected at the morphological level. Moreover, the ability of FHC-silenced K562 cells to respond to the erythroid-specific inducer hemin is almost completely abolished. Interestingly, we found that this new role for FHC is largely mediated via regulation of miR-150, one of the main microRNA implicated in the cell-fate choice of common erythroid/megakaryocytic progenitors. These findings shed further insight into the biological properties of FHCand delineate a role in erythroid differentiation where this protein does not act as a mere iron metabolism-related factor but also as a critical regulator of the expression of genes of central relevance for erythropoiesis.

Validation of a novel shotgun proteomic workflow for the discovery of protein-protein interactions: focus on ZNF521.

The study of protein-protein interactions is increasingly relying on mass spectrometry (MS). The classical approach of separating immunoprecipitated proteins by SDS-PAGE followed by in-gel digestion is long and labor-intensive. Besides, it is difficult to integrate it with most quantitative MS-based workflows, except for stable isotopic labeling of amino acids in cell culture (SILAC). This work describes a fast, flexible and quantitative workflow for the discovery of novel protein-protein interactions. A cleavable cross-linker, dithiobis[succinimidyl propionate] (DSP), is utilized to stabilize protein complexes before immunoprecipitation. Protein complex detachment from the antibody is achieved by limited proteolysis. Finally, protein quantitation is performed via (18)O labeling. The workflow has been optimized concerning (i) DSP concentration and (ii) incubation times for limited proteolysis, using the stem cell-associated transcription cofactor ZNF521 as a model target. The interaction of ZNF521 with the core components of the nuclear remodelling and histone deacetylase (NuRD) complex, already reported in the literature, was confirmed. Additionally, interactions with newly discovered molecular partners of potentially relevant functional role, such as ZNF423, Spt16, Spt5, were discovered and validated by Western blotting.

IRF5 is a target of BCR-ABL kinase activity and reduces CML cell proliferation.

Interferon regulatory factor 5 (IRF5) modulates the expression of genes controlling cell growth and apoptosis. Previous findings have suggested a lack of IRF5 transcripts in both acute and chronic leukemias. However, to date, IRF5 expression and function have not been investigated in chronic myeloid leukemia (CML). We report that IRF5 is expressed in CML cells, where it interacts with the BCR-ABL kinase that modulates its expression and induces its tyrosine phosphorylation. Tyrosine-phosphorylated IRF5 displayed reduced transcriptional activity that was partially restored by imatinib mesylate (IM). Interestingly, a mutant devoid of a BCR-ABL consensus site (IRF5(Y104F)) still presented significant tyrosine phosphorylation. This finding suggests that the oncoprotein phosphorylates additional tyrosine residues or induces downstream signaling pathways leading to further IRF5 phosphorylation. We also found that ectopic expression of IRF5 decreases the proliferation of CML cell lines by slowing their S-G2 transition, increasing the inhibition of BCR-ABL signaling and enhancing the lethality effect observed after treatment with IM, α-2-interferon and a DNA-damaging agent. Furthermore, IRF5 overexpression successfully reduced the clonogenic ability of CML CD34-positive progenitors before and after exposure to the above-indicated cytotoxic stimuli. Our data identify IRF5 as a downstream target of the BCR-ABL kinase, suggesting that its biological inactivation contributes to leukemic transformation.

Expression profiling and functional implications of a set of zinc finger proteins, ZNF423, ZNF470, ZNF521, and ZNF780B, in primary osteoarthritic articular chondrocytes.

Articular chondrocytes are responsible for the maintenance of healthy articulations; indeed, dysregulation of their functions, including the production of matrix proteins and matrix-remodeling proteases, may result in fraying of the tissue and development of osteoarthritis (OA). To explore transcriptional mechanisms that contribute to the regulation of chondrocyte homeostasis and may be implicated in OA development, we compared the gene expression profile of a set of zinc finger proteins potentially linked to the control of chondrocyte differentiation and/or functions (ZNF423, ZNF470, ZNF521, and ZNF780B) in chondrocytes from patients affected by OA and from subjects not affected by OA. This analysis highlighted a significantly lower expression of the transcript encoding ZNF423 in chondrocytes from OA, particularly in elderly patients. Interestingly, this decrease was mirrored by the similarly reduced expression of PPARγ, a known target of ZNF423 with anti-inflammatory and chondroprotective properties. The ZNF521 mRNA instead was abundant in all primary chondrocytes studied; the RNAi-mediated silencing of this gene significantly altered the COL2A/COL1 expression ratio, associated with the maintenance of the differentiated phenotype, in chondrocytes cultivated in alginate beads. These results suggest a role for ZNF423 and ZNF521 in the regulation of chondrocyte homeostasis and warrant further investigations to elucidate their mechanism of action.

Early hematopoietic zinc finger protein prevents tumor cell recognition by natural killer cells.

Early hematopoietic zinc finger/zinc finger protein 521 (EHZF/ZNF521) is a novel zinc finger protein expressed in hematopoietic stem and progenitor cells and is down-regulated during their differentiation. Its transcript is also abundant in some hematopoietic malignancies. Analysis of the changes in the antigenic profile of cells transfected with EHZF cDNA revealed up-regulation of HLA class I cell surface expression. This phenotypic change was associated with an increased level of HLA class I H chain, in absence of detectable changes in the expression of other Ag-processing machinery components. Enhanced resistance of target cells to NK cell-mediated cytotoxicity was induced by enforced expression of EHZF in the cervical carcinoma cell line HeLa and in the B lymphoblastoid cell line IM9. Preincubation of transfected cells with HLA class I Ag-specific mAb restored target cell susceptibility to NK cell-mediated lysis, indicating a specific role for HLA class I Ag up-regulation in the NK resistance induced by EHZF. A potential clinical significance of these findings is further suggested by the inverse correlation between EHZF and MHC class I expression levels, and autologous NK susceptibility of freshly explanted multiple myeloma cells.

Efficient transcriptional targeting of human hematopoietic stem cells and blood cell lineages by lentiviral vectors containing the regulatory element of the Wiskott-Aldrich syndrome gene.

The ability to effectively transduce human hematopoietic stem cells (HSCs) and to ensure adequate but "physiological" levels of transgene expression in different hematopoietic lineages represents some primary features of a gene-transfer vector. The ability to carry, integrate, and efficiently sustain transgene expression in HSCs strongly depends on the vector. We have constructed lentiviral vectors (LV) containing fragments of different lengths of the hematopoietic-specific regulatory element of the Wiskott-Aldrich syndrome (WAS) gene-spanning approximately 1,600 and 170 bp-that direct enhanced green fluorescent protein (EGFP) expression. The performance of vectors carrying the 1,600 and 170 bp fragments of the WAS gene promoter was compared with that of a vector carrying the UbiquitinC promoter in human cord blood CD34(+) cells and their differentiated progeny both in vitro and in vivo in non-obese diabetic mice with severe combined immunodeficiency. All vectors displayed a similar transduction efficiency in CD34(+) cells and promoted long-term EGFP expression in different hematopoietic lineages, with an efficiency comparable to, and in some instances (for example, the 170-bp promoter) superior to, that of the UbiquitinC promoter. Our results clearly demonstrate that LV containing fragments of the WAS gene promoter/enhancer region can promote long-term transgene expression in different hematopoietic lineages in vitro and in vivo and represent suitable and highly efficient vectors for gene transfer in gene-therapy applications for different hematological diseases and for research purposes. In particular, the 170-bp carrying vector, for its reduced size, could significantly improve the transduction/expression of large-size genes.

Zoledronic acid inhibits the growth of leukemic MLL-AF9 transformed hematopoietic cells.

A leukemic in vitro model produced by transducing Cord Blood derived-hematopoietic CD34+ cells with the MLL-AF9 translocation resulting in the oncogenic fusion protein, is used to assess for sensitivity to Zoledronic acid. These cells are practically immortalized and are of myeloid origin. Proliferation, clonogenic and stromal co-culture assays showed that the MLL-AF9 cells were considerably more sensitive to Zoledronic acid than normal hematopoietic CD34+ cells or MS-5 stromal cells. The MLL-AF9 cells were notably more inhibited by Zoledronic acid when cultured as colonies in 3 dimensions, requiring cell-cell contacts compared to suspension expansion cultures. This is coherent with the mechanism of action of Zoledronic acid inhibiting farnesyl diphosphate synthase which results in a block in prenylation of GTPases such that their role in the membrane is compromised for cell-cell contacts. Zoledronic acid can be proposed to target the MLL-AF9 leukemic stem cells before they emerge from the hematopoietic niche, which being in proximity to bone osteoclasts where Zoledronic acid is sequestered can be predicted to result in sufficient levels to result in an anti-leukemic action.

Preclinical activity of sacituzumab govitecan (IMMU-132) in uterine and ovarian carcinosarcomas.

BACKGROUND: Uterine and ovarian carcinosarcomas (CS) are rare cancers with poor prognosis. Sacituzumab-govitecan (SG) is a new class of antibody-drug-conjugate (ADC) targeting the human-trophoblast-cell-surface marker (Trop-2) conjugated with the active metabolite of irinotecan (SN-38). We evaluated the efficacy of SG against biologically aggressive CS. METHODS: Trop-2 expression was evaluated in 10 formalin-fixed-paraffined-embedded (FFPE) CS by immunohistochemistry and 9 primary CS cell-lines by flow-cytometry. One Trop-2 low/negative (SARARK14) and two Trop-2 positive (SARARK4, SARARK9) cell-lines were tested in cell-viability assays . The in vivo antitumor activity of SG was tested in xenografts models (ie, SARARK9) with strong Trop-2 expression. RESULTS: Strong/diffuse staining was seen in 30% (3/10) of FFPE tumors and 33% (3/9) of primary CS cell lines. Trop-2 positive cell-lines (SARARK4, SARARK9) showed higher sensitivity to SG in vitro when compared to Trop-2 low/negative (SARARK14) cell lines. In xenografts, twice-weekly intravenous administration of SG for three weeks showed a significant tumor growth inhibition when compared to control, to ADC control and to the naked AB (p=0.004, p=0.007 and p=0.0007, respectively). SG significantly improved overall survival at 90 days when compared to control groups (p<0.0001). CONCLUSION: SG may represent a novel class of active drugs for carcinosarcomas patients overexpressing Trop-2.

The stem cell-associated transcription co-factor, ZNF521, interacts with GLI1 and GLI2 and enhances the activity of the Sonic hedgehog pathway.

ZNF521 is a transcription co-factor with recognized regulatory functions in haematopoietic, osteo-adipogenic and neural progenitor cells. Among its diverse activities, ZNF521 has been implicated in the regulation of medulloblastoma (MB) cells, where the Hedgehog (HH) pathway, has a key role in the development of normal cerebellum and of a substantial fraction of MBs. Here a functional cross-talk is shown for ZNF521 with the HH pathway, where it interacts with GLI1 and GLI2, the major HH transcriptional effectors and enhances the activity of HH signalling. In particular, ZNF521 cooperates with GLI1 and GLI2 in the transcriptional activation of GLI (glioma-associated transcription factor)-responsive promoters. This synergism is dependent on the presence of the N-terminal, NuRD-binding motif in ZNF521, and is sensitive to HDAC (histone deacetylase) and GLI inhibitors. Taken together, these results highlight the role of ZNF521, and its interaction with the NuRD complex, in determining the HH response at the level of transcription. This may be of particular relevance in HH-driven diseases, especially regarding the MBs belonging to the SHH (sonic HH) subgroup where a high expression of ZNF521 is correlated with that of HH pathway components.

Functional characterization of p.Pro409His variant in HNF1A, a hypomorphic mutation involved in pancreatic ß-cell dysfunction.

AIMS: HNF1A is a gene coding for the transcription factor HNF1-α, mutated in some forms of MODY and type 2 diabetes mellitus characterized by a strong genetic component. The penetrance of HNF1A variants differs considerably; thus, to assess the genetic risk of diabetes in carrier subjects of a HNF1A mutant allele, a functional characterization of mutant forms is of paramount importance. METHODS: The HNF1A gene was sequenced in two patients with partly discordant diabetic phenotype, carrying the p.Pro409His variant. To evaluate the pathogenicity of the variant, we measured the transactivation power of the corresponding P408H HNF1-α mutant mouse form on HNF1-α target promoters. RESULTS: We found a lower but detectable activity of transactivation of the mutant form compared with the wild-type form and we excluded mechanisms of protein degradation or nuclear mislocalization. CONCLUSIONS: The HNF1A mutation p.Pro409His can be considered a mild variant that confers a moderate risk of type 2 diabetes mellitus in heterozygous carriers.

Early hematopoietic zinc finger protein-zinc finger protein 521: a candidate regulator of diverse immature cells.

The early hematopoietic zinc finger protein/zinc finger protein 521 (EHZF/ZNF521) is a recently identified, 1131 amino-acid-long nuclear factor that contains 30 zinc fingers distributed in clusters throughout its sequence. A 13-AA motif, that binds to components of the nuclear remodelling and histone deacetylation (NuRD) complex and is conserved in several trascriptional co-repressors, is located at the amino-terminal end of the molecule. EHZF/ZNF521 expression is high in the most immature cells of the haematopoietic system and declines with differentiation. Its transcript is also abundant in brain, particularly in the cerebellum. Its murine counterpart, Evi3/Zfp521, is enriched in haematopoietic and neural stem cells, in cerebellar granule neuron precursors and in the developing striatum. Enforced expression of EHZF/ZNF521 in haematopoietic progenitors results in their expansion and in inhibition of differentiation. EHZF/ZNF521 is a member of the BMP signalling pathway and an inhibitor of the transcription factor OLF1/EBF1, implicated in the differentiation of neural progenitors and in the specification of the B-cell lineage. EHZF expression is observed in most acute myelogenous leukaemias and is particularly high in those with rearrangements of the MLL gene, where EHZF may contribute to the leukaemic phenotype. EHZF/ZNF521 is also abundant in medulloblastomas and other brain tumours. Taken together, the data available suggest a possible role for this factor in development, stem cell regulation and oncogenesis.

IL-2 signals through Sgk1 and inhibits proliferation and apoptosis in kidney cancer cells.

The interleukin-2 is a cytokine that is essential for lymphocytic survival and function. Ectopic expression of the IL-2 receptor in epithelial tissues has been reported previously, although the functional significance of this expression is still being investigated. We provided novel structural and functional information on the expression of the IL-2 receptor in kidney cancer cells and in other normal and neoplastic human epithelial tissues. In A-498 kidney cancer cells, we showed that IL-2 binding to its own receptor triggers a signal transduction pathway leading to the inhibition of proliferation and apoptosis. We found that the inhibition of proliferation is associated with Erk1/2 dephosphorylation, whereas the survival signals appear to be mediated by Sgk1 activation. This investigation focuses on the IL-2 induced regulation of Sgk1 and describes a role of the IL-2 receptor and Sgk1 in the regulation of epithelial tumor cell death and survival.