Ras has been described to promote proliferation, suppress apoptosis, alter cell\u00a0metabolism, disrupt morphogenesis, promote evasion of the immune system, induce remodeling of the microenvironment and stimulate metastasis. These functions are described below.<\/p>\n
Promotion of proliferation<\/i><\/em> Suppression of apoptosis<\/i><\/em> Alterations in metabolism<\/i><\/em> <\/p>\n Reference:<\/p>\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":" Ras has been described to promote proliferation, suppress apoptosis, alter cell\u00a0metabolism, disrupt morphogenesis, promote evasion of the immune system, induce remodeling of the microenvironment and stimulate metastasis. These functions are […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[20],"tags":[397,395,394],"_links":{"self":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/606"}],"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=606"}],"version-history":[{"count":2,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/606\/revisions"}],"predecessor-version":[{"id":608,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/606\/revisions\/608"}],"wp:attachment":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media?parent=606"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/categories?post=606"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/tags?post=606"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
\n<\/i><\/em>In normal cycling cells, Ras<\/a> transmits mitogenic stimuli required for\u00a0progression through G1. In tumor cells, mutant Ras hijacks the same pathways to\u00a0promote hyperproliferation. For instance, active Ras increases the transcription of\u00a0growth factors that provide the stimulus for proliferation as well as the expression of\u00a0the growth factor receptors themselves. In addition, active Ras upregulates transcription factors involved\u00a0in the expression of cyclin D1. Furthermore, phosphorylation of GSK3\u03b2<\/a>\u00a0by AKT\u00a0downstream of PI3K<\/a> and Ras suppresses the ability of GSK3\u03b2\u00a0to phosphorylate cyclin\u00a0D1 and promote its degradation. The critical nature of cyclin D1 regulation by Ras was tested in mouse models, which revealed that, at least in some cases, Ras-driven tumors were dependent on cyclin D1. Ras is also known to suppress cell cycle inhibitors such as p21 and p27. Finally, Ras is known to stabilize c-myc, a master\u00a0transcription regulator that promotes proliferation, through phosphorylation by ERK\u00a0and prevent c-myc degradation by inhibiting GSK3\u03b2, through PI3K.<\/p>\n
\n<\/i><\/em>Apoptosis, also known as programmed cell death, can be triggered by internal\u00a0signaling from the mitochondria or external signaling through death receptors that\u00a0converge in the activation of caspase-3. These cellular pathways comprise a major\u00a0defense mechanism against tumor maintenance and progression. Interestingly, mouse
\nmodels of mutant Ras-driven melanoma and lung cancer have shown that withdrawal of oncogenic Ras signaling leads to widespread apoptosis.\u00a0Oncogenic Ras can suppress apoptosis by a number of mechanisms.
\nDownstream of PI3K, Ras activation leads to downregulation of BCL-2-homologous\u00a0antagonist\/killer 1 (BAK1) levels, a pro-apoptotic protein that promotes\u00a0mitochondrial-dependent apoptosis, and increases the levels of inhibitors of apoptosis (IAPs). Ras activation also leads to\u00a0Raf-dependent downregulation of the pro-apoptotic transcriptional repressor prostate\u00a0apoptosis response 4 (PAR4) as well as upregulation of the anti-apoptotic BCL-2 and\u00a0apoptosis regulator with caspase recruitment domain (ARC). Both PI3K and Raf\u00a0pathways lead to phosphorylation of BAD, which prevents its pro-apoptotic functions. Incontrast, Ras has been shown to have proapoptotic functions through Raf-mediated induction of p53 in addition to RASSF1,\u00a0NORE1, MST1 and JNK mediated regulation of caspase-3, BAK1 and\u00a0Bcl-2 associated X protein (BAX). However, these pro-apoptotic functions are\u00a0hypothesized to be more important in normal cells.<\/p>\n
\n<\/i><\/em>Many cancer cells shift their primary metabolic pathway from oxidative\u00a0phosphorylation to anaerobic glycolysis, a change known as the Warburg effect. It is\u00a0theorized that the Warburg effect occurs because anaerobic glycolysis better provides\u00a0macromolecules needed as precursors for cell growth. Interestingly, the same\u00a0oncogenic pathways that regulate proliferation also regulate metabolic pathways. For instance, c-myc overexpression promotes both\u00a0proliferation and glutamine addiction while PI3K regulates glucose metabolism. A primary role of oncogenic Ras is to upregulate expression of hypoxiainducible factor la (HIFla), which binds to constitutively expressed HIFip to form\u00a0the HIF transcription factor. In normal cells, HIF signaling results from sensing low\u00a0oxygen levels and logically leads to a shift to anaerobic glycolysis. In Ras mutant\u00a0cells, PI3K activates AKT<\/a>, which activates mTOR-mediated translation of HIFla. Ras also increases transcription of the glucose transporter\u00a0GLUT1, increasing the availability of glucose in the cell.\u00a0Furthermore, Ras increases the levels of key enzymes in glycolysis, including\u00a0hexokinase and phosphofructokinase. A more recently\u00a0discovered contribution of Ras to metabolism is an upregulation of autophagy.<\/p>\n