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The GNA13-RhoA signaling axis suppresses expression of tumor protective Kallikreins.

Publication ,  Journal Article
Teo, CR; Casey, PJ; Rasheed, SAK
Published in: Cell Signal
October 2016

Gα13 (encoded by GNA13 gene) is the alpha subunit of a heterotrimeric G-protein that mediates signaling through specific G-protein-coupled receptors (GPCRs). Increased GNA13 expression has been observed in metastatic breast cancer cells. Recently, we have shown that enhanced GNA13 signaling in MCF-10a cells, a benign breast cancer cell line increased its invasiveness. Previous studies have reported that Kallikrein-related peptidases (KLKs 1-15) are down-regulated in breast tumors and may have a tumor protective function. However, the mechanisms that lead to the down-regulation of KLK genes in breast cancer are yet to be elucidated. We found that enhanced GNA13 signaling represses KLK gene expression in breast cancer, and undertook examination of the mechanisms involved. A microarray analysis revealed down-regulation of several members of the Kallikrein-related peptidases (KLK) gene family, namely KLK5, KLK6, KLK7, KLK8 and KLK10, in MCF-10a lines with enhanced GNA13 protein expression. Using real-time PCR and promoter analysis, we identified that the mRNA expression and promoter activities of these KLKs are suppressed upon enforced expression of GNA13 in MCF-10a cells. Using Rhotekin pull-down assays, we identified that GNA13 suppressed Rho-A activation and protein levels in MCF-10a cells. Blocking Rho-A activation using C3-toxin or by inhibiting its down-stream effector, Rho-associated kinase (ROCK), reduced the above-mentioned KLK mRNAs in MCF-10A cells. Importantly, in a metastatic breast cancer cell line MDA-MB-157, knock down of GNA13 alone was sufficient to induce the expression KLK mRNAs. Taken together, our findings suggested that enhanced GNA13 signaling down-regulates KLK gene transcription. The ability of enhanced GNA13 signaling to suppress KLK gene expression appears at least in part due to the ability of enhanced GNA13 signaling to negatively impact Rho/ROCK-signaling.

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Published In

Cell Signal

DOI

EISSN

1873-3913

Publication Date

October 2016

Volume

28

Issue

10

Start / End Page

1479 / 1488

Location

England

Related Subject Headings

  • rhoA GTP-Binding Protein
  • rho-Associated Kinases
  • Signal Transduction
  • Reproducibility of Results
  • RNA, Small Interfering
  • RNA, Messenger
  • Promoter Regions, Genetic
  • Kallikreins
  • Humans
  • Gene Knockdown Techniques
 

Citation

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Teo, C. R., Casey, P. J., & Rasheed, S. A. K. (2016). The GNA13-RhoA signaling axis suppresses expression of tumor protective Kallikreins. Cell Signal, 28(10), 1479–1488. https://doi.org/10.1016/j.cellsig.2016.07.001
Teo, Cui Rong, Patrick J. Casey, and Suhail Ahmed Kabeer Rasheed. “The GNA13-RhoA signaling axis suppresses expression of tumor protective Kallikreins.Cell Signal 28, no. 10 (October 2016): 1479–88. https://doi.org/10.1016/j.cellsig.2016.07.001.
Teo CR, Casey PJ, Rasheed SAK. The GNA13-RhoA signaling axis suppresses expression of tumor protective Kallikreins. Cell Signal. 2016 Oct;28(10):1479–88.
Teo, Cui Rong, et al. “The GNA13-RhoA signaling axis suppresses expression of tumor protective Kallikreins.Cell Signal, vol. 28, no. 10, Oct. 2016, pp. 1479–88. Pubmed, doi:10.1016/j.cellsig.2016.07.001.
Teo CR, Casey PJ, Rasheed SAK. The GNA13-RhoA signaling axis suppresses expression of tumor protective Kallikreins. Cell Signal. 2016 Oct;28(10):1479–1488.
Journal cover image

Published In

Cell Signal

DOI

EISSN

1873-3913

Publication Date

October 2016

Volume

28

Issue

10

Start / End Page

1479 / 1488

Location

England

Related Subject Headings

  • rhoA GTP-Binding Protein
  • rho-Associated Kinases
  • Signal Transduction
  • Reproducibility of Results
  • RNA, Small Interfering
  • RNA, Messenger
  • Promoter Regions, Genetic
  • Kallikreins
  • Humans
  • Gene Knockdown Techniques