K-Ras and B-Raf oncogenes inhibit colon epithelial polarity establishment through up-regulation of c-myc

Magudia, Kirti; Lahoz, Agustín; Hall, Alan

doi:10.1083/jcb.201202108

Cited by 52 publications

(51 citation statements)

References 38 publications

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“…Transfection with KRAS V12 inhibited lumen formation to yield glands that were cell-filled and solid in appearance (Figure 5A, 5B), in accord with previous findings [33]. Furthermore, KRAS V12 transfection suppressed apical localization of PRKCZ in Caco-2 glands (Figure 5A, 5C) and inhibited 1,25(OH) 2 D 3 rescue of Caco-2 ShPTEN gland morphology (Figure 5D, 5E).…”

Section: Resultssupporting

confidence: 89%

Vitamin D3 suppresses morphological evolution of the cribriform cancerous phenotype

et al. 2016

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Development of cribriform morphology (CM) heralds malignant change in human colon but lack of mechanistic understanding hampers preventive therapy. This study investigated CM pathobiology in three-dimensional (3D) Caco-2 culture models of colorectal glandular architecture, assessed translational relevance and tested effects of 1,25(OH)2D3, the active form of vitamin D. CM evolution was driven by oncogenic perturbation of the apical polarity (AP) complex comprising PTEN, CDC42 and PRKCZ (phosphatase and tensin homolog, cell division cycle 42 and protein kinase C zeta). Suppression of AP genes initiated a spatiotemporal cascade of mitotic spindle misorientation, apical membrane misalignment and aberrant epithelial configuration. Collectively, these events promoted “Swiss cheese-like” cribriform morphology (CM) comprising multiple abnormal “back to back” lumens surrounded by atypical stratified epithelium, in 3D colorectal gland models. Intestinal cancer driven purely by PTEN-deficiency in transgenic mice developed CM and in human CRC, CM associated with PTEN and PRKCZ readouts. Treatment of PTEN-deficient 3D cultures with 1,25(OH)2D3 upregulated PTEN, rapidly activated CDC42 and PRKCZ, corrected mitotic spindle alignment and suppressed CM development. Conversely, mutationally-activated KRAS blocked 1,25(OH)2D3 rescue of glandular architecture. We conclude that 1,25(OH)2D3 upregulates AP signalling to reverse CM in a KRAS wild type (wt), clinically predictive CRC model system. Vitamin D could be developed as therapy to suppress inception or progression of a subset of colorectal tumors.

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Section: Resultssupporting

confidence: 89%

Vitamin D3 suppresses morphological evolution of the cribriform cancerous phenotype

et al. 2016

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“…KRAS is reported to have a key role in cellular signal transduction and its mutation appears to be crucial in colorectal, pancreatic, and other cancers (Chen et al, 2009;Yu et al, 2010;Magudia et al, 2012). Activation of KRAS signaling could stimulate multiple downstream pathways, including the RAS/MAPK/ERK and PI3K/Akt, thus promoting tumorigenesis (Schubbert et al, 2007;Bodemann and White, 2008).…”

Section: Discussionmentioning

confidence: 98%

miR-134 Functions as a Tumor Suppressor in Cell Proliferation and Epithelial-to-Mesenchymal Transition by Targeting KRAS in Renal Cell Carcinoma Cells

Liu

Zhang

Qian

et al. 2015

DNA and Cell Biology

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Aberrant microRNAs (miRNAs) are reported to contribute to the pathogenesis of most human malignancies. The miRNA, miR-134, has been found to be downregulated in renal cell carcinoma (RCC), but its function in the disease is unknown. The aims of this study were to detect the expression of miR-134 in human RCC samples and explore its function in RCC cell lines. Real-time qualitative polymerase chain reaction (qPCR) was used to quantify miR-134 in human RCC samples. Assays for cell cycle, viability, migration, and invasion were performed to assess the phenotypic changes in RCC cells. A luciferase reporter assay was carried out to confirm whether KRAS (Kirsten rat sarcoma viral oncogene homolog) is a direct target of miR-134. Western blot was used to identify the potential signaling pathways that had an impact on RCC cell growth and alterations of markers for epithelial-mesenchymal transition (EMT), which affected metastasis by miR-134. miR-134 was found to be downregulated in RCC samples (p<0.05), while overexpression of miR-134 suppressed proliferation (p<0.05) by triggering G1/G0 cell cycle arrest (p<0.05). Forced expression of miR-134 could also inhibit migration (p<0.05) and invasion (p<0.05) by blocking EMT in RCC cell lines. KRAS was identified as a target of miR-134, and miR-134 may act as a tumor suppressor through the KRAS-related MAPK/ERK pathway other than PI3K/AKT signaling. Thus, miR-134 may function as a tumor suppressor in cell proliferation and EMT by targeting KRAS in RCC cells.

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“…Previous studies have demonstrated that loss of polarity is associated with late stage or metastatic tumors where cancer cells undergo epithelial-mesenchymal transition (1,34,35). The function of several oncogenic proteins and tumor suppressors (such as HER2/ERBB2, KRAS, and LKB1) has also been connected to their ability to regulate the integrity of epithelial polarity (9,(35)(36)(37)(38). In addition, it has been suggested that loss of epithelial polarity may lead to aberrant activation of receptor tyrosine kinase (RTK) due to disruption of asymmetrical distribution of the receptors (39).…”

Section: Discussionmentioning

confidence: 99%

Pleckstrin Homology (PH) Domain Leucine-rich Repeat Protein Phosphatase Controls Cell Polarity by Negatively Regulating the Activity of Atypical Protein Kinase C

Xiong

Wen

et al. 2016

Journal of Biological Chemistry

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Edited by Henrik DohlmanThe proper establishment of epithelial polarity allows cells to sense and respond to signals that arise from the microenvironment in a spatiotemporally controlled manner. Atypical PKCs (aPKCs) are implicated as key regulators of epithelial polarity. However, the molecular mechanism underlying the negative regulation of aPKCs remains largely unknown. In this study, we demonstrated that PH domain leucine-rich repeat protein phosphatase (PHLPP), a novel family of Ser/Thr protein phosphatases, plays an important role in regulating epithelial polarity by controlling the phosphorylation of both aPKC isoforms. Altered expression of PHLPP1 or PHLPP2 disrupted polarization of Caco2 cells grown in 3D cell cultures as indicated by the formation of aberrant multi-lumen structures. Overexpression of PHLPP resulted in a decrease in aPKC phosphorylation at both the activation loop and the turn motif sites; conversely, knockdown of PHLPP increased aPKC phosphorylation. Moreover, in vitro dephosphorylation experiments revealed that both aPKC isoforms were substrates of PHLPP. Interestingly, knockdown of PKC, but not PKC, led to similar disruption of the polarized lumen structure, suggesting that PKC likely controls the polarization process of Caco2 cells. Furthermore, knockdown of PHLPP altered the apical membrane localization of aPKCs and reduced the formation of aPKC-Par3 complex. Taken together, our results identify a novel role of PHLPP in regulating aPKC and cell polarity.Establishing the polarity of epithelial cells is crucial for the maintenance of tissue homeostasis. Increasing evidence has suggested that disruption of polarity promotes the malignant progression of cancer cells. It has been well documented that epithelial cells (including those in the gastrointestinal tract) become polarized during the differentiation process (1). The polarization process is characterized by the formation of specialized junctions between neighboring cells and subsequent separation of two plasma membrane domains: the apical surface facing the external medium and the basolateral surface connected to adjacent cells and extracellular matrix (2). The apical and basolateral membranes are segregated by two highly organized junctions, the tight and adherens junctions, assembled at the site of mammalian cell-cell contacts (3-5). As a major component of the Par complex, aPKCs 2 including PKC and PKC, are known to phosphorylate a number of polarity proteins, including Par3, LgL, Crumbs, and Lin5/NuMA, thereby exerting its regulatory roles in cellular polarization (6). Previous studies have suggested that a precise control of aPKC activity is required for the proper establishment of epithelial cell-cell junction and cell polarity (7,8). Loss of polarity has been associated with increased cell migration and metastasis during tumor progression (1, 9).Differing from conventional and novel PKCs, aPKCs are insensitive to diacylglycerol-and Ca 2ϩ -mediated activation due to the lack of functional C1 and C2 domains (10). As a result...

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K-Ras and B-Raf oncogenes inhibit colon epithelial polarity establishment through up-regulation of c-myc

Abstract: ERK-mediated up-regulation of c-myc by K-Ras or B-Raf oncogenes disrupts the establishment of apical/basolateral polarity independently of its effect on proliferation.

Cited by 52 publications

References 38 publications

Vitamin D3 suppresses morphological evolution of the cribriform cancerous phenotype

Vitamin D3 suppresses morphological evolution of the cribriform cancerous phenotype

miR-134 Functions as a Tumor Suppressor in Cell Proliferation and Epithelial-to-Mesenchymal Transition by Targeting KRAS in Renal Cell Carcinoma Cells

Pleckstrin Homology (PH) Domain Leucine-rich Repeat Protein Phosphatase Controls Cell Polarity by Negatively Regulating the Activity of Atypical Protein Kinase C

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