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Dual Functions for OVAAL in Initiation of RAF/MEK/ERK Prosurvival Signals and Evasion of p27-mediated Cellular Senescence

Dual Functions for OVAAL in Initiation of RAF/MEK/ERK Prosurvival Signals and Evasion of p27-mediated Cellular Senescence

Ben Sang, Yuan Yuan Zhang, Su Tang Guo, Ling Fei Kong, Qiong Cheng, Guang Zhi Liu, Rick F Thorne, Xu Dong Zhang, Lei Jin, Mian Wu

Proc Natl Acad Sci U S A. 2018 Dec 11;115(50):E11661-E11670.

PMID: 30478051

Abstract:

Long noncoding RNAs (lncRNAs) function through a diverse array of mechanisms that are not presently fully understood. Here, we sought to find lncRNAs differentially regulated in cancer cells resistant to either TNF-related apoptosis-inducing ligand (TRAIL) or the Mcl-1 inhibitor UMI-77, agents that act through the extrinsic and intrinsic apoptotic pathways, respectively. This work identified a commonly up-regulated lncRNA, ovarian adenocarcinoma-amplified lncRNA (OVAAL), that conferred apoptotic resistance in multiple cancer types. Analysis of clinical samples revealed OVAAL expression was significantly increased in colorectal cancers and melanoma in comparison to the corresponding normal tissues. Functional investigations showed that OVAAL depletion significantly inhibited cancer cell proliferation and retarded tumor xenograft growth. Mechanically, OVAAL physically interacted with serine/threonine-protein kinase 3 (STK3), which, in turn, enhanced the binding between STK3 and Raf-1. The ternary complex OVAAL/STK3/Raf-1 enhanced the activation of the RAF protooncogene serine/threonine-protein kinase (RAF)/mitogen-activated protein kinase kinase 1 (MEK)/ERK signaling cascade, thus promoting c-Myc-mediated cell proliferation and Mcl-1-mediated cell survival. On the other hand, depletion of OVAAL triggered cellular senescence through polypyrimidine tract-binding protein 1 (PTBP1)-mediated p27 expression, which was regulated by competitive binding between OVAAL and p27 mRNA to PTBP1. Additionally, c-Myc was demonstrated to drive OVAAL transcription, indicating a positive feedback loop between c-Myc and OVAAL in controlling tumor growth. Taken together, these results reveal that OVAAL contributes to the survival of cancer cells through dual mechanisms controlling RAF/MEK/ERK signaling and p27-mediated cell senescence.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP220904836-B	Raf1 Kinase Inhibitor I - CAS 220904-83-6		220904-83-6	Price
AP518303203	UMI-77		518303-20-3	Price

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