Matrix Metalloproteinase Induction of Rac1b, a Key Effector of Lung Cancer Progression

Stallings-Mann, Melody; Waldmann, Jens; Zhang, Ying; Miller, Erin; Gauthier, Mona L.; Visscher, Daniel W.; Downey, Gregory P.; Radisky, Evette S.; Fields, Alan P.; Radisky, Derek C.

doi:10.1126/scitranslmed.3004062

Cited by 95 publications

(100 citation statements)

References 66 publications

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“…RAC1b, a splice variant of RAC1 that predominantly exists in the GTP-bound active form, has been previously shown to be highly expressed in breast and colon cancers (Jordan et al 1999;Schnelzer et al 2000). More recently, two papers reported that RAC1b promotes K-rasinduced lung tumorigenesis, and that RAC1b stimulates epithelial-mesenchymal transition and spontaneous tumor formation (Stallings-Mann et al 2012;Zhou et al 2012). We observed near twofold up-regulation of total RAC1 expression levels in all three lung tumors.…”

Section: Differential Isoform Usage Revealed By Rna-seqsupporting

confidence: 61%

Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events

Liu¹,

Lee²,

Jiang³

et al. 2012

Genome Res.

184

137

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Lung cancer is a highly heterogeneous disease in terms of both underlying genetic lesions and response to therapeutic treatments. We performed deep whole-genome sequencing and transcriptome sequencing on 19 lung cancer cell lines and three lung tumor/normal pairs. Overall, our data show that cell line models exhibit similar mutation spectra to human tumor samples. Smoker and never-smoker cancer samples exhibit distinguishable patterns of mutations. A number of epigenetic regulators, including KDM6A, ASH1L, SMARCA4, and ATAD2, are frequently altered by mutations or copy number changes. A systematic survey of splice-site mutations identified 106 splice site mutations associated with cancer specific aberrant splicing, including mutations in several known cancer-related genes. RAC1b, an isoform of the RAC1 GTPase that includes one additional exon, was found to be preferentially up-regulated in lung cancer. We further show that its expression is significantly associated with sensitivity to a MAP2K (MEK) inhibitor PD-0325901. Taken together, these data present a comprehensive genomic landscape of a large number of lung cancer samples and further demonstrate that cancer-specific alternative splicing is a widespread phenomenon that has potential utility as therapeutic biomarkers. The detailed characterizations of the lung cancer cell lines also provide genomic context to the vast amount of experimental data gathered for these lines over the decades, and represent highly valuable resources for cancer biology.

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Section: Differential Isoform Usage Revealed By Rna-seqsupporting

confidence: 61%

Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events

Liu¹,

Lee²,

Jiang³

et al. 2012

Genome Res.

184

137

View full text Add to dashboard Cite

show abstract

“…One particular example is the tumor-related splicing variant Rac1b, an isoform of the signaling GTPase Rac1 (Matos et al 2003), in which a usually skipped exon 3b is retained. The resulting protein isoform Rac1b is overexpressed in a specific subtype of colorectal tumors and required to sustain tumor cell survival (Jordan et al 1999;) but was also reported in breast, lung, and thyroid tumors (Schnelzer et al 2000;Radisky et al 2005;Liu et al 2012;Stallings-Mann et al 2012;Silva et al 2013;Zhou et al 2013). Interestingly, Rac1b was found to be predominantly in the signaling-competent GTP-bound conformation (Schnelzer et al 2000;Matos et al 2003;Fiegen et al 2004;Radisky et al 2005), so that small changes in its expression level yield significant cellular responses.…”

Section: Introductionmentioning

confidence: 98%

Phosphorylation of SRSF1 by SRPK1 regulates alternative splicing of tumor-related Rac1b in colorectal cells

Gonçalves

Henriques

Pereira

et al. 2014

RNA

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The premessenger RNA of the majority of human genes can generate various transcripts through alternative splicing, and different tissues or disease states show specific patterns of splicing variants. These patterns depend on the relative concentrations of the splicing factors present in the cell nucleus, either as a consequence of their expression levels or of post-translational modifications, such as protein phosphorylation, which are determined by signal transduction pathways. Here, we analyzed the contribution of protein kinases to the regulation of alternative splicing variant Rac1b that is overexpressed in certain tumor types. In colorectal cells, we found that depletion of AKT2, AKT3, GSK3β, and SRPK1 significantly decreased endogenous Rac1b levels. Although knockdown of AKT2 and AKT3 affected only Rac1b protein levels suggesting a post-splicing effect, the depletion of GSK3β or SRPK1 decreased Rac1b alternative splicing, an effect mediated through changes in splicing factor SRSF1. In particular, the knockdown of SRPK1 or inhibition of its catalytic activity reduced phosphorylation and subsequent translocation of SRSF1 to the nucleus, limiting its availability to promote the inclusion of alternative exon 3b into the Rac1 pre-mRNA. Altogether, the data identify SRSF1 as a prime regulator of Rac1b expression in colorectal cells and provide further mechanistic insight into how the regulation of alternative splicing events by protein kinases can contribute to sustain tumor cell survival.

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“…5). Moreover, RAC1b overexpression has been implicated in the induction of EMT (40,41). EMT is a form of epithelial plasticity that has been associated with tumor metastasis and, accordingly, RAC1b was reported to have a key role in the malignant progression of breast and lung tumors (28,36,41).…”

Section: Discussionmentioning

confidence: 99%

RAC1b overexpression in papillary thyroid carcinoma: a role to unravel

Silva¹,

Carmo²,

Bugalho

2013

European Journal of Endocrinology

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Context: The BRAF V600E mutation is the most frequent genetic alteration in papillary thyroid carcinoma (PTC). In colorectal cancer, BRAF V600E was described to functionally cooperate with RAC1b, a hyperactive splice variant of the small GTPase RAC1, to sustain cell survival. This interplay has never been investigated in PTCs.Objective: We aimed to analyze the expression of RAC1b in PTC and correlate its expression with BRAF V600E mutational status, histopathological features, and clinical outcome. Patients and methods: Sixty-one patients and 87 samples (61 PTCs and 26 normal thyroid tissues) were included. Patients were divided into two groups based on longitudinal evolution and final outcome. RAC1b expression levels were determined by quantitative RT-PCR and western blotting. Results: RAC1b was expressed in thyroid and overexpressed in 46% of PTCs. Neither RAC1b overexpression nor V600E mutation correlated with histopathological features classically associated with worse prognosis. RAC1b overexpression was significantly associated with both V600E mutation (PZ0.0008) and poor clinical outcome (PZ0.0029). Whereas BRAF V600E alone did not associate with patient outcome (PZ0.2865), the association of RAC1b overexpression with BRAF V600E was overrepresented in the group with poorer clinical outcome (PZ0.0044). Conclusions: Present results document, for the first time, expression of RAC1b in normal thyroid cells as well as overexpression in a subset of PTCs. Furthermore, they suggest a possible interplay between BRAF V600E and RAC1b contributing to poor clinical outcome. Future studies are needed to clarify the oncogenic potential of RAC1b in thyroid carcinogenesis.

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Matrix Metalloproteinase Induction of Rac1b, a Key Effector of Lung Cancer Progression

Cited by 95 publications

References 66 publications

Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events

Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events

Phosphorylation of SRSF1 by SRPK1 regulates alternative splicing of tumor-related Rac1b in colorectal cells

RAC1b overexpression in papillary thyroid carcinoma: a role to unravel

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