{"id":609,"date":"2017-02-16T04:39:36","date_gmt":"2017-02-16T09:39:36","guid":{"rendered":"http:\/\/www.bocsci.com\/blog\/?p=609"},"modified":"2017-02-16T04:39:36","modified_gmt":"2017-02-16T09:39:36","slug":"the-functions-of-ras-part-two","status":"publish","type":"post","link":"https:\/\/www.bocsci.com\/blog\/the-functions-of-ras-part-two\/","title":{"rendered":"The Functions of Ras\u2014part two"},"content":{"rendered":"

Morphogenesis and cell polarity<\/i><\/em>
\n<\/i><\/em>Changes in the morphology and polarity of cells are clearly essential for tumor progression and metastasis. In two-dimensional (2D) culture, it has been observed that oncogenic K-Ras expression disruptsapical polarity and causes multilayering of\u00a0Madin-Darby canine kidney (MDCK) cells that normally grow as a monolayer. It is not clear, however, whether this is due to a loss of\u00a0contact inhibition of growth, or to a direct effect of Ras signaling to polarity\u00a0machinery. In the mouse embryo, increased ERK1\/2 signaling disrupted proper\u00a0mitotic spindle orientation, and it is possible that a defect in spindle orientation could\u00a0underlie the multilayering phenotype.
\nTight junctions are known to play an important role in maintaining cell\u00a0polarity. It has been shown that oncogenic Ras disrupts localization of the tight\u00a0junction components ZO-1 and occludin as well as inhibits E-cadherin expression and\u00a0that this can be rescued by MEK<\/a> inhibition). These results are\u00a0consistent with another study indicating that oncogenic Raf downregulates occludin to\u00a0disrupt tight junctions. Whether Ras expression affects the\u00a0barrier function of tight junctions is not clear and may depend on the cell type.\u00a0Induction of epithelial-to-mesenchymal transition (EMT) is an important\u00a0hallmark of cancers and is associated with a complete loss of epithelial characteristics\u00a0including cell-cell adhesion. A more mesenchymal morphology is clearly seen in\u00a0MDCK cells expressing active Ras or Raf and is sometimes associated with decreased\u00a0E-cadherin. Either alone, or in cooperation with the TGF\u03b2\u00a0pathway, oncogenic Ras represses transcription of E-cadherin via the SNAIL and SLUG\u00a0transcription factors.\u00a0Ras also promotes methylation of the E-cadherin promoter as well as increases\u00a0E-cadherin degradation. Other aspects of\u00a0EMT which contribute to invasion and metastasis will be discussed fiirther in Section\u00a01B.4.7.<\/p>\n

Evasion of immune response<\/i><\/em>
\n<\/i><\/em>Oncogenic Ras reduces the ability of the immune system to recognize tumor\u00a0cells. First, Ras reduces the expression of major immunohistocompatibility complexes (MHCs) that are normally present on the surface of all cells, reducing the\u00a0immunogenicity of tumor cells. This does not occur by changes in transcriptional regulation of MHCs, but rather by compromised peptide processing machinery. Second, T cells that are specific to mutant Ras are often anergic, perhaps because of the recruitment of regulatory T cells that are immunosuppressive.
\nRemodeling of microenvironment<\/i><\/em>
\n<\/i><\/em>Tumor cells remodel their microenvironment by promoting growth factors\u00a0required for angiogenesis, which allow tumor cells to receive the oxygen and nutrients\u00a0they require, as well as degrading the extracellular matrix (ECM) to permit vessel\u00a0formation and aid tumor cell invasion. Oncogenic Ras has been shown to regulate both\u00a0these processes. Downstream of Raf, for instance, active ERK phosphorylates HIFla,\u00a0increasing HIF transcriptional activity to upregulate vascular endothelial growth factor\u00a0(VEGF) expression, while PI3K activation has a similar effect. In addition, Ras increases cyclooxygenase-2\u00a0(COX-2)<\/a> levels, which produces prostaglandins and leads to increased expression of\u00a0VEGF.<\/p>\n

Oncogenic Ras plays a role in the loss of cell adhesion to matrix that is\u00a0characteristic of EMT. For instance, oncogenic Ras leads to downregulation of\u00a0integrin (31 chain maturation in HD6-4 colon epithelial cells. In\u00a0addition, oncogenic Ras reduces cell surface expression of aipi integrin receptor that\u00a0binds collagen and laminin as well as the a5pi integrin receptor that binds fibronectin\u00a0in SW 480 colon adenocarcinoma cells.<\/p>\n

In order for tumor cells to invade and metastasize, many changes are necessary\u00a0in the actin and microtubule cytoskeletons among other pathways to promote frontrear polarity and cell migration. As Rho GTPases are master cytoskeletal regulators, it\u00a0is likely through these proteins that oncogenic Ras stimulates cytoskeletal changes and
\nestablishes asymmetry within cells. It is already\u00a0known, for instance, that PI3K activates multiple Rac GEFs that result in the\u00a0activation of Rac, a Rho GTPase family member. Ras also\u00a0directly regulates the Rac GEF Tiaml. Furthermore, RalA and\u00a0RalB, which are activated downstream of the Ras effector RalGDS, regulate the Rho\u00a0GAP domain containing protein RalBPl. Finally, Ras promotes\u00a0Rho activation downstream of MEK, by translocating pi 90 Rho-GAP out of the\u00a0cytoplasm and into an inaccessible cytoskeletal compartment.\u00a0Another important requirement for tumor cells to successful invade through the\u00a0basement membrane and metastasize is to avoid matrix deprivation-induced apoptosis,\u00a0also known as anoikis. Multiple studies report that oncogenic Ras prevents anoikis by\u00a0downregulating proapoptotic Bak and preventing the downregulation of the\u00a0antiapoptotic BC1-XL. The effects of Ras on Bak are downstream of PI3K, but oftenthe effects are surprisingly independent of both PI3K and Raf.<\/p>\n

Reference\uff1a<\/h4>\n

Kirti Magudia. K-RAS AND B-RAF ONCOGENES INHIBIT POLARITY ESTABLISHMENT\u00a0THROUGH ERK-MEDIATED REGULATION OF C-MYC\u00a0IN COLON EPITHELIAL CELLS<\/p>\n","protected":false},"excerpt":{"rendered":"

Morphogenesis and cell polarity Changes in the morphology and polarity of cells are clearly essential for tumor progression and metastasis. In two-dimensional (2D) culture, it has been observed that oncogenic […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[20],"tags":[400,398],"_links":{"self":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/609"}],"collection":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/comments?post=609"}],"version-history":[{"count":1,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/609\/revisions"}],"predecessor-version":[{"id":610,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/609\/revisions\/610"}],"wp:attachment":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media?parent=609"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/categories?post=609"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/tags?post=609"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}