The Rac1 splice form Rac1b promotes K-ras-induced lung tumorigenesis

Zhou, Chun; Licciulli, Silvia; Avila, Jacqueline L.; Cho, Miyoung; Troutman, Scott; Jiang, Ping; Kossenkov, Andrew V.; Showe, Louise C.; Liu, Qin; Vachani, Anil; Albelda, Steven Μ.; Kissil, Joseph L.

doi:10.1038/onc.2012.99

Cited by 95 publications

(92 citation statements)

References 20 publications

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“…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). Our finding that RAC1b overexpression significantly associates with a poor outcome in PTCs may be indicative of a similar role for RAC1b in the progression of thyroid carcinomas.…”

Section: Discussionsupporting

confidence: 57%

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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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Section: Discussionsupporting

confidence: 57%

“…It was first identified in skin and epithelial tissue of the intestinal tract (26). RAC1b expression was also documented in breast tissue and was found to be overexpressed in colorectal and lung cancer (23,26,27,28).…”

Section: Introductionmentioning

confidence: 99%

RAC1b overexpression in papillary thyroid carcinoma: a role to unravel

Silva¹,

Carmo²,

Bugalho

2013

European Journal of Endocrinology

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“…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: 99%

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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“…155 Expression of Rac1b has also been found in breast cancer and lung cancer. 156,157 Rac1b has been shown to be involved in MMP-3-mediated malignant transformation of mammary epithelial cells. MMP-3 induces the expression of Rac1b which increases the levels of cellular ROS, leading to expression of the transcription factor Snail, which induces epithelial-mesenchymal transition (EMT) as well as oxidative damage to DNA and genomic instability.…”

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confidence: 99%

Rho GTPases: Regulation and roles in cancer cell biology

Haga

Ridley²

2016

Small GTPases

417

390

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Rho GTPases are well known for their roles in regulating cell migration, and also contribute to a variety of other cellular responses. They are subdivided into 2 groups: typical and atypical. The typical Rho family members, including RhoA, Rac1 and Cdc42, cycle between an active GTP-bound and inactive GDP-bound conformation, and are regulated by GEFs, GAPs and GDIs, whereas atypical Rho family members have amino acid substitutions that alter their ability to interact with GTP/GDP and hence are regulated by different mechanisms. Both typical and atypical Rho GTPases contribute to cancer progression. In a few cancers, RhoA or Rac1 are mutated, but in most cancers expression levels and/or activity of Rho GTPases is altered. Rho GTPase signaling could therefore be therapeutically targeted in cancer treatment.

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The Rac1 splice form Rac1b promotes K-ras-induced lung tumorigenesis

Cited by 95 publications

References 20 publications

RAC1b overexpression in papillary thyroid carcinoma: a role to unravel

RAC1b overexpression in papillary thyroid carcinoma: a role to unravel

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

Rho GTPases: Regulation and roles in cancer cell biology

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