PTBP1
Polypyrimidine tract-binding protein 1 (PTB) (57 kDa RNA-binding protein PPTB-1) (Heterogeneous nuclear ribonucleoprotein I) (hnRNP I) [PTB]
Publications[править]
Continuous neuronal survival is vital for mammals because mammalian brains have limited regeneration capability. After neurogenesis, suppression of apoptosis is needed to ensure a neuron's long-term survival. Here we describe a robust genetic program that intrinsically attenuates apoptosis competence in neurons. Developmental downregulation of the splicing regulator PTBP1 in immature neurons allows neural-specific splicing of the evolutionarily conserved Bak1 microexon 5. Exon 5 inclusion triggers nonsense-mediated mRNA decay (NMD) and unproductive translation of Bak1 transcripts (N-Bak mRNA), leading to suppression of pro-apoptotic BAK1 proteins and allowing neurons to reduce apoptosis. Germline heterozygous ablation of exon 5 increases BAK1 proteins exclusively in the brain, inflates neuronal apoptosis, and leads to early postnatal mortality. Therefore, neural-specific exon 5 splicing and depletion of BAK1 proteins uniquely repress neuronal apoptosis. Although apoptosis is important for development, attenuation of apoptosis competence through neural-specific splicing of the Bak1 microexon is essential for neuronal and animal survival.
MeSH Terms
- Animals
- Apoptosis
- Brain
- Cell Line, Tumor
- Cells, Cultured
- Female
- Heterogeneous-Nuclear Ribonucleoproteins
- Male
- Mice
- Mice, Inbred C57BL
- Mutation
- Neural Stem Cells
- Neurogenesis
- Nonsense Mediated mRNA Decay
- Polypyrimidine Tract-Binding Protein
- RNA Splicing
- bcl-2 Homologous Antagonist-Killer Protein
Keywords
- AS-NMD
- BAK
- BCL2 family proteins
- NMD
- PTB
- PTBP
- PTBP2
- UPF2
- alternative splicing
- cell death
- neural development
- neurogenesis
- neuronal lifespan
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
Oncogene-induced senescence is a potent tumor-suppressive response. Paradoxically, senescence also induces an inflammatory secretome that promotes carcinogenesis and age-related pathologies. Consequently, the senescence-associated secretory phenotype (SASP) is a potential therapeutic target. Here, we describe an RNAi screen for SASP regulators. We identified 50 druggable targets whose knockdown suppresses the inflammatory secretome and differentially affects other SASP components. Among the screen candidates was PTBP1. PTBP1 regulates the alternative splicing of genes involved in intracellular trafficking, such as EXOC7, to control the SASP. Inhibition of PTBP1 prevents the pro-tumorigenic effects of the SASP and impairs immune surveillance without increasing the risk of tumorigenesis. In conclusion, our study identifies SASP inhibition as a powerful and safe therapy against inflammation-driven cancer.
MeSH Terms
- Alternative Splicing
- Animals
- Cell Proliferation
- Cell Transformation, Neoplastic
- Cellular Senescence
- Female
- Gene Expression Regulation, Neoplastic
- Heterogeneous-Nuclear Ribonucleoproteins
- Humans
- Inflammation
- MCF-7 Cells
- Mice, Inbred C57BL
- Mice, Transgenic
- Neoplasms
- Paracrine Communication
- Phenotype
- Polypyrimidine Tract-Binding Protein
- RNA Interference
- Signal Transduction
- Tumor Burden
- Vesicular Transport Proteins
Keywords
- EXOC7
- Oncogene-induced senescence
- PTBP1
- RNAi screen
- SASP
- alternative splicing
- senescence