Serine-Arginine Protein Kinase 1 Overexpression Is Associated with Tumorigenic Imbalance in Mitogen-Activated Protein Kinase Pathways in Breast, Colonic, and Pancreatic Carcinomas

Abstract

Aberrant patterns of pre-mRNA processing are typical of human malignancies, yet the mechanisms responsible for these changes remain undefined. We have recently shown overexpression of a core splice regulatory protein, serinearginine protein kinase 1 (SRPK1), in dysplastic and neoplastic pancreatic ductular cells. In the present study, we have established that SRPK1 levels are similarly up-regulated in breast and colonic tumors where its expression increases coordinately with tumor grade. Targeting SRPK1 for inhibition using small interfering RNA in breast and colonic tumor cell lines in vitro resulted in both increased apoptotic potential and enhanced cell killing after treatment with gemcitabine and cisplatin. Recent reports have described multifaceted interactions between the mitogen-activated protein kinase (MAPK) and AKT signaling networks and the splice regulatory machinery. Consequently, we have shown that targeted inhibition of SRPK1 in tumor cells results in reduced phosphorylation of MAPK3, MAPK1, and AKT. Alterations in the splice pattern and resulting expression of MAPK kinase are implicated in mediating the antitumoral effects resulting from SRPK1 down-regulation. The up-regulation of SRPK1 in multiple cancers and its ability to regulate multiple relevant signaling pathways provide support for developing agents to inhibit this kinase for possible broad application to treat epithelial cancers. [Cancer Res 2007;67(5):2072-80]

MicroRNA-9 Inhibition of Cell Proliferation and Identification of Novel miR-9 Targets by Transcriptome Profiling in Breast Cancer Cells

“…Silencing of LARP1 increased apoptosis in HeLa cells (43). SRPK1 (SRSF protein kinase 1) functions in alternative splicing and has been implicated in many cancer types (44,(65)(66)(67)(68). Silencing of SRPK1 increased apoptotic potential in breast and colonic tumor cell lines (44) and decreased proliferative capacity in leukemic cells (69).…”

“…3A). CCNG1, MTHFD2, LARP1, and SRPK1 were selected on the basis of their previous implications in breast cancer (41)(42)(43)(44), whereas AP3B1 and MTHFD1L were selected as potential biomarkers. All of these genes were predicted to have one miR-9 binding site, except MTHFD2, which has two predicted miR-9 binding sites (Fig.…”

Alternative Splicing of SLC39A14 in Colorectal Cancer is Regulated by the Wnt Pathway

“…SRPK1 is known to activate SR proteins by phosphorylation enabling them to migrate to the nucleus and participate in the splicing process (14). SRPK1 has been reported to be up-regulated in several human cancers including colon and breast where a knockdown of SRPK1 was shown to increase the number of cells undergoing apoptosis (13). Splicing factor binding prediction analysis showed that SRSF1 binding motifs were found primarily in exon 4B of SLC39A14, which could explain the increased presence of 4B when either SRPK1 or SRSF1 is up-regulated.…”

“…AS plays a critical role during development, and defects in AS have been implicated in numerous human diseases, including cancer (10 -12). Several SR proteins are activated by phosphorylation of their serines by SRSF protein kinase 1 (SRPK1), which is up-regulated in colon, breast, and pancreatic cancer (13). The best described SRPK1 target is serine/arginine-rich splicing factor 1 (SRSF1, formerly known as SF2/ASF) (14,15), an essential splicing factor that participates in both constitutive and AS, and which was recently shown to be a proto-oncogene (12) supporting the involvement of AS in cancer development.…”

Myocardial Gene Expression Associated with Genetic Cardiac Hypertrophy in the Absence of Hypertension

“…The over-expression in old HHR of the guanine nucleotide binding protein gene (Gng5), Rab12 (a member of the Ras oncogene family) and mitogen activated protein kinase 1 (Mapk1) further suggests a role for the Ras/ MAPK signaling pathway in the etiology of cardiac enlargement in the HHR. Evidence that MAPK1 (27)(28)(29), MAPK14 (30,31) and MAP2K4 (32) are involved in normal and abnormal tissue growth further strengthens the possibility that these are key enzymes in the cardiotrophic process in the HHR. However, the cause and effect relationship between the activity of these enzymes and the elevated cardiac size of the HHR remains to be determined.…”