The microarray experiment was independently repeated in triplicate for each sample group

ther alter the expression level of critical genes or their nucleotide sequence to generate gain- or loss-of-function mutant gene products. Although point mutations in core components of the spliceosome were recently discovered using wholegenome sequencing approaches, PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19809862 reports from various tumor types revealed that splicing factors mostly show increased expression levels. Concerning SRSF1, overexpression was reported in tumors from colon, thyroid, small intestine, kidney, lung, liver, pancreas, and breast. In childhood acute lymphoblastic leukemia SRSF1 BioMed Research International was further found to be upregulated together with protein arginine methyltransferase PRMT1, which is order CF-101 involved in promoting SRSF1 nuclear localization. The overexpression of SRSF1 in tumors has been related to several alternative mechanisms. First, in breast tumors and breast cancer cell lines amplification of the SFRS1 gene at chromosomal location 17q23 was detected and the increased DNA copy number correlated with elevated SRSF1 mRNA levels. Second, the SRSF1 gene is a target of MYC, a potent oncogenic transcription factor overexpressed in many different tumor types that has pleiotropic effects on cancer cell biology. MYC binds directly to the SRSF1 promoter and activates transcription. Both genes were found coexpressed in lung and breast carcinomas and MYC depletion downregulates SRSF1 expression in lung cancer cell lines. Third, the above-mentioned negative feedback loop, in which SRSF1 promotes an increase in unproductive splice variants of its own transcripts, can be subverted in the presence of splicing regulator SAM68. Changes in expression or phosphorylation of SAM68 were found to promote the formation of full-length SRSF1 transcripts, thus leading to increased SRSF1 protein levels. SAM68 phosphorylation depends on ERK/MAP kinase activity, which is frequently augmented in human tumors. Together, this indicates that SRSF1 overexpression is in general the consequence of other preceding tumor-initiating genetic changes but contributes to further tumor progression. Two apparently opposing consequences of SRSF1 overexpression on cancer cell biology have been described: the induction of oncogene-induced senescence and the malignant transformation of cells. On the one hand, SRSF1 overexpression leads to the formation of a nucleoplasmic complex with the ribosomal protein RPL5 and the E3-ubiquitin ligase MDM2, which normally ubiquitylates the p53 tumorsuppressor protein leading to its proteolytic degradation. Complex formation inhibits MDM2 and thus p53 protein levels increase and trigger a cellular senescence response, which normally is part of a ribosomal stress pathway. Because the ability of SRSF1 overexpression to activate a tumorsuppressing senescence response is dependent on an intact p53 pathway, the identified SRSF1-overexpressing tumor types revealed characteristics of p53 inactivation. On the other hand, SRSF1 can act as an oncogene since a twofold increase in expression can transform immortalized rodent fibroblasts and human mammary epithelial cells. In these models, SRSF1 overexpression promoted cell proliferation and antiapoptotic pathways, mainly reflecting the combined effects of several alternative splicing variants which were activated by the concentrationdependent changes in SRSF1 availability. Some of these specific variants have been characterized, as detailed below, but probably represent just the tip of the iceberg. One group of identifie