Ore proximal location, this only occurs if CPC is dimerized. The role of dimerization appears to be to simply double the interaction surfaces of CPC with centromere receptors to provide tighter binding and full function. The CD44 gene undergoes extensive alternative splicing and generates CD44 variants that contain one or more of a set of variable exons. When the variable exons are excluded, the CD44 standard isoform PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19851335 is produced. Interestingly, CD44v promotes cell growth by forming co-receptor complexes with receptor tyrosine kinases and activating Ras/MAPK signaling66. By contrast, CD44s mediates cell contact inhibition67. Upon mitogenic activation, Ras/MAPK pathway promotes alternative splicing of CD44, generating a variable exon 6 containing CD44v6 isoform65, 6870. The newly synthesized CD44v6 isoform augments the action of RTKs, including Met and EGFR, and further promotes Ras/MAPK signaling. These actions constitute a positive feedback circuit that amplifies Ras/MAPK signaling, stimulating cell proliferation by controlling G1-S transition65. When utilized by tumor cells, this CD44 alternative splicing-mediated positive feedback loop could cause uncontrolled tumor cell proliferation and oncogenic transformation. The mechanisms by which Ras/MAPK stimulates CD44 alternative splicing have been studied. Ras/MAPK signaling facilitates the activity of splicing factors Sam68 and SRm160, most likely via phosphorylation of these splicing factors, to stimulate CD44 variable exon inclusion.70, 71 Moreover, using a mouse model of Kras-induced lung adenocarcinoma, we found that CD44v expression is Neuromedin N web preferentially upregulated in lung adenocarcinomas. Ablation of the CD44 gene attenuates lung tumor formation and prolongs the survival of these mice.72 These observations suggest that an aberrant set point of alternative splicing could alter intracellular signaling, engage cell proliferation, and influence tumor progression. The critical role of alternative splicing in promoting sustained proliferation signals in cancer is further demonstrated by Cyclin D1. Cyclin D1 controls cell cycle progression by regulating cyclin-dependent kinase activities. While p63 and p73 mutations are rare, aberrant expression of their splice isoforms was frequently observed in human Vonoprazan site cancers84, however, the functional consequences of this are not yet well studied. Resisting cell death Apoptosis is a programmed cell death that serves as a natural barrier to cancer cells. However, as tumors progress, cancer cells become insensitive to apoptotic signals, eventually leading to advanced malignancy and chemo-resistance85, 86. The apoptotic pathway 
consists of both upstream regulators and downstream effectors. The death receptor FAS is an upstream regulator that receives extracellular death signals induced by the Fas ligand and processes the signals to the intrinsic apoptotic pathway that carries out the final execution. One of the initial executioners of apoptosis is Caspase-9. Activation of Caspase-9 initiates a cascade of proteolysis 
leading to consumption and clearance of the cell. Importantly, both Fas and Caspase-9 are regulated by alternative splicing. Splice isoforms of these proteins can have opposing functions to either stimulate or inhibit apoptosis87, 88. In the case of the death receptor Fas, inclusion of variable exon 6 results in the production of the membrane-bound Fas that promotes apoptosis, whereas skipping of variable exon 6 produces a soluble form of Fas tha.Ore proximal location, this only occurs if CPC is dimerized. The role of dimerization appears to be to simply double the interaction surfaces of CPC with centromere receptors to provide tighter binding and full function. The CD44 gene undergoes extensive alternative splicing and generates CD44 variants that contain one or more of a set of variable exons. When the variable exons are excluded, the CD44 standard isoform PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19851335 is produced. Interestingly, CD44v promotes cell growth by forming co-receptor complexes with receptor tyrosine kinases and activating Ras/MAPK signaling66. By contrast, CD44s mediates cell contact inhibition67. Upon mitogenic activation, Ras/MAPK pathway promotes alternative splicing of CD44, generating a variable exon 6 containing CD44v6 isoform65, 6870. The newly synthesized CD44v6 isoform augments the action of RTKs, including Met and EGFR, and further promotes Ras/MAPK signaling. These actions constitute a positive feedback circuit that amplifies Ras/MAPK signaling, stimulating cell proliferation by controlling G1-S transition65. When utilized by tumor cells, this CD44 alternative splicing-mediated positive feedback loop could cause uncontrolled tumor cell proliferation and oncogenic transformation. The mechanisms by which Ras/MAPK stimulates CD44 alternative splicing have been studied. Ras/MAPK signaling facilitates the activity of splicing factors Sam68 and SRm160, most likely via phosphorylation of these splicing factors, to stimulate CD44 variable exon inclusion.70, 71 Moreover, using a mouse model of Kras-induced lung adenocarcinoma, we found that CD44v expression is preferentially upregulated in lung adenocarcinomas. Ablation of the CD44 gene attenuates lung tumor formation and prolongs the survival of these mice.72 These observations suggest that an aberrant set point of alternative splicing could alter intracellular signaling, engage cell proliferation, and influence tumor progression. The critical role of alternative splicing in promoting sustained proliferation signals in cancer is further demonstrated by Cyclin D1. Cyclin D1 controls cell cycle progression by regulating cyclin-dependent kinase activities. While p63 and p73 mutations are rare, aberrant expression of their splice isoforms was frequently observed in human cancers84, however, the functional consequences of this are not yet well studied. Resisting cell death Apoptosis is a programmed cell death that serves as a natural barrier to cancer cells. However, as tumors progress, cancer cells become insensitive to apoptotic signals, eventually leading to advanced malignancy and chemo-resistance85, 86. The apoptotic pathway consists of both upstream regulators and downstream effectors. The death receptor FAS is an upstream regulator that receives extracellular death signals induced by the Fas ligand and processes the signals to the intrinsic apoptotic pathway that carries out the final execution. One of the initial executioners of apoptosis is Caspase-9. Activation of Caspase-9 initiates a cascade of proteolysis leading to consumption and clearance of the cell. Importantly, both Fas and Caspase-9 are regulated by alternative splicing. Splice isoforms of these proteins can have opposing functions to either stimulate or inhibit apoptosis87, 88. In the case of the death receptor Fas, inclusion of variable exon 6 results in the production of the membrane-bound Fas that promotes apoptosis, whereas skipping of variable exon 6 produces a soluble form of Fas tha.