The DEAD box protein p68: a crucial regulator of AKT/FOXO3a signaling axis in oncogenesis
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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| Title |
The DEAD box protein p68: a crucial regulator of AKT/FOXO3a signaling axis in oncogenesis
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| Creator |
Sarkar, M
Khare, V Guturi, KKN Das, N Ghosh, Mrinal K |
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| Subject |
Cancer Biology and Inflammatory Disorder Division
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| Description |
Increased abundance of proto-oncogene AKT and reduced expression of tumor suppressor Forkhead box O3 (FOXO3a), the
downstream target of AKT, is frequent in carcinogenesis. Mechanistic insights of AKT gene regulation are limited. DEAD box RNA helicase p68 is overexpressed in various cancers and acts as a transcriptional co-activator of several transcription factors, including β-catenin. Here, we report a novel mechanism of p68-mediated transcriptional activation of AKT, and its ensuing effect on FOXO3a,
in colon carcinogenesis. Interestingly, we found that the expression of p68 and AKT exhibits strong positive correlation in normal and colon carcinoma patient samples. In addition, p68 increased both AKT messenger RNA (mRNA) and protein, enhanced AKT promoter activity in multiple colon cancer cell lines. Conversely, p68 knockdown led to reduced AKT mRNA and protein, diminished AKT promoter activity. Here, we demonstrated that p68 occupies AKT promoter with β-catenin as well as nuclear factor-κB (NF-κB)
and cooperates with these in potentiating AKT transcription. Furthermore, p68 and FOXO3a expression followed inverse correlation in the same set of colon carcinoma samples. We observed that p68 significantly reduced FOXO3a protein level in an AKTdependent
manner. Studies in primary tumors and metastatic lung nodules generated in mice colorectal allograft model, using
syngeneic cells stably expressing p68, corroborated our in vitro findings. Hence, a new mechanism of oncogenesis is attributed to p68 by upregulation of AKT and consequent nuclear exclusion and degradation of tumor suppressor FOXO3a
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| Date |
2015
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2451/1/Oncogene_(2015)_34%2C_5843%E2%80%935856.pdf
Sarkar, M and Khare, V and Guturi, KKN and Das, N and Ghosh, Mrinal K (2015) The DEAD box protein p68: a crucial regulator of AKT/FOXO3a signaling axis in oncogenesis. The Oncogene, 34. pp. 5843-5856. |
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| Relation |
http://dx.doi.org/10.1038/onc.2015.42
http://www.eprints.iicb.res.in/2451/ |
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