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SSeCKS/Gravin/AKAP12 attenuates expression of proliferative and angiogenic genes during suppression of v-Src-induced
Yongzhong Liu1, Lingqiu Gao, Irwin H Gelman
1Mucosal Immunology Unit, National Institutes of Health, Bethesda, MD 20892, USA. yoliu@mail.nih.gov
Background:
SSeCKS 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.
Methods:
We 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.
Results:
SSeCKS re-expression resulted in the attenuation of critical Src-induced proliferative and pro-angiogenic gene expression including Afp, Hif-1alpha, Cdc20a and Pdgfr-beta, and conversely, SSeCKS induced several cell cycle regulatory genes such as Ptpn11, Gadd45a, Ptplad1, Cdkn2d (p19), and Rbbp7.
Conclusion:
Our data provide further evidence that SSeCKS can suppress Src-induced oncogenesis by modulating gene expression downstream of Src kinase activity.
Insights
The protein kinase C substrate SSeCKS suppresses cancer growth by altering gene expression. Re-expressing SSeCKS inhibits cancer cell proliferation and blood vessel formation, offering potential therapeutic strategies.
Area of Science:
- Molecular oncology
- Signal transduction pathways
- Gene expression regulation
Background:
- SSeCKS (Src-suppressed C-kinase substrate) is a tumor suppressor downregulated in various cancers.
- SSeCKS exhibits kinase scaffolding and metastasis-suppression activities.
- Previous studies showed SSeCKS re-expression inhibits oncogenic growth without affecting Src kinase activity.
Purpose of the Study:
- To investigate the impact of SSeCKS on gene expression in the context of Src-induced oncogenesis.
- To identify specific genes regulated by SSeCKS and v-Src signaling.
Main Methods:
- Utilized cDNA microarrays and semi-quantitative RT-PCR.
- Analyzed gene expression changes under conditions of SSeCKS expression, v-Src activation, and combined SSeCKS re-expression with active v-Src.
Main Results:
- SSeCKS re-expression attenuated Src-induced expression of proliferative and pro-angiogenic genes (e.g., Afp, Hif-1alpha, Cdc20a, Pdgfr-beta).
- SSeCKS induced expression of cell cycle regulatory genes (e.g., Ptpn11, Gadd45a, Ptplad1, Cdkn2d, Rbbp7).
Conclusions:
- SSeCKS suppresses Src-induced oncogenesis by modulating downstream gene expression.
- These findings highlight SSeCKS's role as a key regulator in cancer signaling pathways.
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