Abstract
BackgroundSSeCKS is a major protein kinase C substrate with kinase scaffolding and metastasis-suppressor activity whose expression is severely downregulated in Src- and Ras-transformed fibroblast and epithelial cells and in human prostate, breast, and gastric cancers. We previously used NIH3T3 cells with tetracycline-regulated SSeCKS expression plus a temperature-sensitive v-Src allele to show that SSeCKS re-expression inhibited parameters of v-Src-induced oncogenic growth without attenuating in vivo Src kinase activity.MethodsWe use cDNA microarrays and semi-quantitative RT-PCR analysis to identify changes in gene expression correlating with i) SSeCKS expression in the absence of v-Src activity, ii) activation of v-Src activity alone, and iii) SSeCKS re-expression in the presence of active v-Src.ResultsSSeCKS re-expression resulted in the attenuation of critical Src-induced proliferative and pro-angiogenic gene expression including Afp, Hif-1α, Cdc20a and Pdgfr-β, and conversely, SSeCKS induced several cell cycle regulatory genes such as Ptpn11, Gadd45a, Ptplad1, Cdkn2d (p19), and Rbbp7.ConclusionOur data provide further evidence that SSeCKS can suppress Src-induced oncogenesis by modulating gene expression downstream of Src kinase activity.
Highlights
Src Suppressed C Kinase Substrate (SSeCKS) is a major protein kinase C substrate with kinase scaffolding and metastasissuppressor activity whose expression is severely downregulated in Src- and Ras-transformed fibroblast and epithelial cells and in human prostate, breast, and gastric cancers
SSeCKS, originally identified as a transcriptionally-suppressed gene in v-src and ras-transformed rodent fibroblast cells [1], is the orthologue of human GRAVIN/ AKAP12 gene that encodes a kinase-scaffolding protein [2] that is targeted as an autoantigen in some cases of myasthenia gravis [3]
Cells S2-6 cells are NIH3T3 cells that encode a tetracyclineregulated tTA transactivator (Tet-OFF), S24 cells are S2-6 cells encoding a tet-regulated rat SSeCKS cDNA, and S24/ ts72v-Src cells express temperature-sensitive v-Src whose kinase activity is only active at the permissive temperature (PT = 35°C), as described previously [6]
Summary
SSeCKS is a major protein kinase C substrate with kinase scaffolding and metastasissuppressor activity whose expression is severely downregulated in Src- and Ras-transformed fibroblast and epithelial cells and in human prostate, breast, and gastric cancers. SSeCKS does not grossly alter the Src-mediated tyrosine phosphorylation of cellular substrates in vivo [6], strongly suggesting that SSeCKS suppresses tumorigenicity by re-establishing controls on downstream cytoskeletal and signaling pathways. It remains unclear which pathways are regulated by SSeCKS during tumor or metastasis suppression
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
