Serine/threonine-protein kinase 3 (EC 2.7.11.1) (Mammalian STE20-like protein kinase 2) (MST-2) (STE20-like kinase MST2) (Serine/threonine-protein kinase Krs-1) [Contains: Serine/threonine-protein kinase 3 36kDa subunit (MST2/N); Serine/threonine-protein kinase 3 20kDa subunit (MST2/C)] [KRS1] [MST2]
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Dual functions for OVAAL in initiation of RAF/MEK/ERK prosurvival signals and evasion of p27-mediated cellular senescence.
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.
MeSH Terms
- Animals
- Apoptosis
- Cell Line, Tumor
- Cell Proliferation
- Cell Survival
- Cellular Senescence
- Colorectal Neoplasms
- Cyclin-Dependent Kinase Inhibitor p27
- Heterografts
- Humans
- MAP Kinase Signaling System
- Melanoma
- Mice
- Mice, Nude
- Protein Stability
- Protein-Serine-Threonine Kinases
- Proto-Oncogene Proteins c-myc
- Proto-Oncogene Proteins c-raf
- RNA, Long Noncoding
- RNA, Messenger
- TNF-Related Apoptosis-Inducing Ligand
Keywords
- OVAAL
- c-Myc
- p27
- proliferation
- senescence
развернуть
Organ-specific alteration in caspase expression and
STK3 proteolysis during the aging process.
Caspases and their substrates are key mediators of apoptosis and strongly implicated in various physiological processes. As the serine/threonine kinase family is involved in apoptosis and serine/threonine kinase 3 (STK3) is a recently identified caspase-6 substrate, we assessed the expression and cleavage of STK3 in murine peripheral organs and brain regions during the aging process. We also assessed caspase-3, -6, -7, and -8 expression and activity in order to delineate potential mechanism(s) underlying the generation of the STK3 fragments observed and their relation to the apoptotic pathway. We demonstrate for the first time the cleavage of STK3 by caspase-7 and show that STK3 protein levels globally increase throughout the organism with age. In contrast, caspase-3, -6, -7, and -8 expression and activity vary significantly among the different organs analyzed suggesting differential effects of aging on the apoptotic mechanism and/or nonapoptotic functions of caspases throughout the organism. These results further our understanding of the role of caspases and their substrates in the normal aging process and highlight a potential role for STK3 in neurodegeneration.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Brain
- Caspases
- Gene Expression
- Male
- Mice, Inbred C57BL
- Neurodegenerative Diseases
- Organ Specificity
- Protein-Serine-Threonine Kinases
- Proteolysis
Keywords
- Aging
- Apoptosis
- Brain region
- Caspases
- Peripheral organs
- Serine/threonine kinase 3