Essay Example on The progression of Melanoma









The progression of melanoma has not only been attributed to certain genetic alterations but also to some epigenetic modifications such as chromatin modification methylation and remodeling These oncogenic mutations disrupt the normal operation of cellular pathways which leads to regulate several transcription factors that cause apoptosis cell cycle deregulation and cell proliferation Several studies have demonstrated that multiple cellular pathways are associated with melanomagenesis and the mechanism of these pathways will be briefly discussed as follows Sarkar et al 2015 1 1 MAPK pathway The Mitogen Activated Protein Kinase MAPK pathway consists of RAS RAF MEK and ERK proteins and more than 80 of all cutaneous melanomas are determined by the activation of MAPK pathway which is regulated by cytokines heteromeric G protein coupled receptors and tyrosine kinases receptors Mozuraitiene et al 2015 The dysregulation of MAPK pathway is frequently occurred due to the mutations in BRAF genes leading to unchecked cell division invasion migration evasion of cellular senescence angiogenesis and apoptosis Inamdar Madhunapantula Robertson 2010 RAF itself is activated by the small G protein in RAS and form the complex with RAS 

This activated RAS RAF complex activates the ERK MAPK via MEK phosphorylation to promote the cell proliferation Mozuraitiene et al 2015 Mckibbin 2015 1 2 PI3K AKT Pathway PI3K AKT AKT pathway is one of the major signaling networks in cancer In addition to regulate essential cellular processes it plays a significant role in development and progression of melanoma Both MAPK and PI3K AKT pathways are constitutively active as the result of PTEN inactivation and BRAF mutation Michael 2012 The PI3K AKT pathway is activated by mitogenic stimuli and growth factors for an instance AKT pathway is activated through the binding of a ligand to G protein coupled receptor GPCRs or tyrosine kinases receptor RTK and binding of GTP to RAS protein Michael 2012 Yajima 2012 In response to these signals PI3K is activated and it phosphorylates PI phosphatidylinositols to PIP3 phosphatidylinositol 3 phosphate to activate serine threonine kinase AKT Phosphate and tensin homolog PTEN is a tumor suppressor gene which acts as a negative regulator on the PI3K AKT pathway It dephosphorylates PIP3 to PI to inactivate PI and stop subsequent downstream pathways The PI3K protein cannot be inhibited when the PTEN is mutated which result in regulating the activity of the AKT Maehama Dixon 1998 Bertolotto 2013 Activated AKT facilitates the cell proliferation cell survival antiapoptotic signaling and cancer promotion through regulation of mammalian target of rapamycin mTOR Dhawan et al 2002 Park Zeng Glazer 2001 Figure

1 The mechanism of MAPK pathway and PI3K AKT pathway 1 3 CDK Pathway Cyclin dependent kinases CDK plays a key role in regulating cell cycle and it controls the major checkpoints G1 S G2 and M in cell cycle through the phosphorylation of selected proteins Johnson Kornbluth 2012 Therefore CDK s overexpression and or overactivation leads to lose the checkpoint integrity which result in unchecked cell proliferation Sheppard McArthur 2013 The major gene involved in CDK pathway is cyclin dependent kinase inhibitor CDKN2A which locus on chromosome 9p21 Two tumor suppressor proteins namely p14ARF and p16INK4a are encoded on chromosome9p21 which helps to keep cells from uncontrolled growing and rapid dividing U S National Library of Medicine 2018 When the mutation happens in the CDKN2A gene p16INK4a protein specifically interacts with two proteins namely CDK4 and CDK6 Cell division protein kinase and inhibit the formation of active Cyclin D CDK complex that phosphorylates the RB1 retinoblastoma protein The p16NK4a loss of function regulates the activation of CDK4 and CDK6 which in turn activates the transcription factor E2F to promote the G1 S cell cycle progression Palmieri et al 2013 P14ARF regulates the functions of mouse double minute 2 homolog

MDM2 which is mainly known to act as a cellular antagonist of the tumor suppressor p53 protein that plays a key role in inducing cell cycle arrest and or apoptosis Sionov Hayon Haupt 2013 Therefore its activity must be tightly regulated to maintain the normal cell growth and their development MDM2 act as an E3 ubiquitin ligase which can induce the p53 protein degradation by polyubiquitination and proteasome processing to downregulate the protein level of p53 Honda Tanaka Yasuda 1997 Ponnuswamy Hupp Fahraeous 2012 In response to the inactivation of CDKN2A and loss of function of p14ARF the degradation of p53 is inhibited which leads to induce the activity of p21 and block the Cyclin E CDK activity Inactivation of p14ARF negatively regulates the cell cycle and promotes the cell proliferation Panayi et al 2013 Kudchadkar 2010 1 4 p53 pathway The p53 is a tumor suppressor protein which is encoded at theTP53 gene It plays a major role as a transcription repressor by regulating transcriptional expressions of downstream pathways which induce the apoptosis cell growth arrest or senescence The progression of cell cycle DNA repairs angiogenesis and genomic integrity are also regulated by p53 protein Hunten et al 2013 However in melanoma cancer p53 protein is not frequently mutated Panayi et al 2013 MDM2 plays an important role in the cell via interacting with many proteins for an instance MDM2 interacts with DNA polymerase for DNA synthesis and repair Asahara et al 2003 and it interacts with several proteins such as DNA methyltransferase p107 Rb E2F 1 complex p21 to regulate the cell cycle Nag et al 2013 As many studies demonstrated MDM2 protein interactions involved in most of the cellular pathways such as DNA repairs cell mortality and apoptosis and these interactions either directly or indirectly affect the activities of p53 Therefore MDM2 p53 interaction is playing major role in normal cell growth and development

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