Elevated Expression of the Serine-Arginine Protein Kinase 1 Gene in Ovarian Cancer and Its Role in Cisplatin Cytotoxicity In Vitro

Odunsi, Kunle; Mhawech‐Fauceglia, Paulette; Andrews, Chris; Beck, Amy; Amuwo, Olajumoke; Lele, Shashikant; Black, Jennifer D.; Huang, Ruea Yea

doi:10.1371/journal.pone.0051030

Cited by 46 publications

(50 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our observation agrees with reduced SRPK1 expression in certain cancer cell lines (Hayes et al, 2006) or tumors (Krishnakumar et al, 2008; Odunsi et al, 2012; Schenk et al, 2004). Examination of a panel of human colon cancers revealed that SRPK1 was undetectable in multiple tumors compared to surrounding non-cancerous tissues (Figure 2D).…”

Section: Resultssupporting

confidence: 89%

Both Decreased and Increased SRPK1 Levels Promote Cancer by Interfering with PHLPP-Mediated Dephosphorylation of Akt

et al. 2014

View full text Add to dashboard Cite

Akt activation is a hallmark of human cancers. Here we report a critical mechanism for regulation of Akt activity by the splicing kinase SRPK1, a downstream Akt target for transducing growth signals to regulate splicing. Surprisingly, we find that SRPK1 has a tumor suppressor function because ablation of SRPK1 in mouse embryonic fibroblasts induces cell transformation. We link the phenotype to constitutive Akt activation from genome-wide phosphoproteomics analysis and discover that down-regulated SRPK1 impairs the recruitment of the Akt phosphatase PHLPP1 to Akt. Interestingly, SRPK1 overexpression is also tumorigenic because excess SRPK1 squelches PHLPP1. Thus, aberrant SRPK1 expression in either direction induces constitutive Akt activation, providing a mechanistic basis for previous observations that SRPK1 is down-regulated in some cancer contexts and up-regulated in others.

show abstract

Section: Resultssupporting

confidence: 89%

Both Decreased and Increased SRPK1 Levels Promote Cancer by Interfering with PHLPP-Mediated Dephosphorylation of Akt

et al. 2014

View full text Add to dashboard Cite

show abstract

“…31 siRNA mediated silencing of SRPK1 in ovarian cancer cell lines resulted in reduced cell proliferation and increased sensitivity to cisplatin. 34 Inhibition of SRPK1 using siRNA or pharmacological inhibitor suppressed VEGF expression and decreased melanoma growth in vivo. Studies by Zhou et al, have shown that SRPKs constitute a major branch of Akt signaling pathway in EGF mediated alternate splicing.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of splicing proteins in head and neck squamous cell carcinoma

Radhakrishnan

Nanjappa

Raja

et al. 2016

Cancer Biology & Therapy

View full text Add to dashboard Cite

ABSRTRACTSignaling plays an important role in regulating all cellular pathways. Altered signaling is one of the hallmarks of cancers. Phosphoproteomics enables interrogation of kinase mediated signaling pathways in biological systems. In cancers, this approach can be utilized to identify aberrantly activated pathways that potentially drive proliferation and tumorigenesis. To identify signaling alterations in head and neck squamous cell carcinoma (HNSCC), we carried out proteomic and phosphoproteomic analysis of HNSCC cell lines using a combination of tandem mass tag (TMT) labeling approach and titanium dioxide-based enrichment. We identified 4,920 phosphosites corresponding to 2,212 proteins in six HNSCC cell lines compared to a normal oral cell line. Our data indicated significant enrichment of proteins associated with splicing. We observed hyperphosphorylation of SRSF protein kinase 2 (SRPK2) and its downstream substrates in HNSCC cell lines. SRPK2 is a splicing kinase, known to phosphorylate serine/arginine (SR) rich domain proteins and regulate splicing process in eukaryotes. Although genome-wide studies have reported the contribution of alternative splicing events of several genes in the progression of cancer, the involvement of splicing kinases in HNSCC is not known. In this study, we studied the role of SRPK2 in HNSCC. Inhibition of SRPK2 resulted in significant decrease in colony forming and invasive ability in a panel of HNSCC cell lines. Our results indicate that phosphorylation of SRPK2 plays a crucial role in the regulation of splicing process in HNSCC and that splicing kinases can be developed as a new class of therapeutic target in HNSCC.

show abstract

“…An increase in the intracellular level of SRPK1, a major kinase of SR proteins, has been demonstrated to be critical in the regulation of the alternative splicing profile of malignant cells (Gout et al 2012;Odunsi et al 2012;. Mutations of Wilms' tumor suppressor gene (WT1) lead to the up-regulation of SRPK1, which diminishes the SRSF1-mediated up-regulation of VEGF165b (Amin et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Elevated SRPK1 lessens apoptosis in breast cancer cells through RBM4-regulated splicing events

Lin

Tarn

et al. 2014

RNA

View full text Add to dashboard Cite

Imbalanced splicing of premessenger RNA is typical of tumorous malignancies, and the regulatory mechanisms involved in several tumorigenesis-associated splicing events are identified. Elevated expression of serine-arginine protein kinase 1 (SRPK1) may participate in the pathway responsible for the dysregulation of splicing events in malignant tumor cells. In this study, we observed a correlation between the cytoplasmic accumulation of RNA-binding motif protein 4 (RBM4) and up-regulated SRPK1 in breast cancer cells. The production of the IR-B and MCL-1 S transcripts was induced separately by the overexpression of RBM4 and SRPK1 gene silencing. Overexpressed RBM4 simultaneously bound to the CU-rich elements within the MCL-1 exon2 and the downstream intron, which subsequently facilitated the exclusion of the regulated exon. Breast cancer cells are deprived of apoptotic resistance through the RBM4-mediated up-regulation of the IR-B and MCL-1 S transcripts. These findings suggest that the splicing events regulated by the SRPK1-RMB4 network may contribute to tumorigenesis through altered sensitivity to apoptotic signals in breast cancer cells.

show abstract

Elevated Expression of the Serine-Arginine Protein Kinase 1 Gene in Ovarian Cancer and Its Role in Cisplatin Cytotoxicity In Vitro

Cited by 46 publications

References 34 publications

Both Decreased and Increased SRPK1 Levels Promote Cancer by Interfering with PHLPP-Mediated Dephosphorylation of Akt

Both Decreased and Increased SRPK1 Levels Promote Cancer by Interfering with PHLPP-Mediated Dephosphorylation of Akt

Dysregulation of splicing proteins in head and neck squamous cell carcinoma

Elevated SRPK1 lessens apoptosis in breast cancer cells through RBM4-regulated splicing events

Contact Info

Product

Resources

About