Ptbp1-KO Mouse

Ptbp1, also known as Polypyrimidine tract-binding protein 1, is a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family. It plays a key role in alternative splicing of precursor mRNA and RNA metabolism. It is ubiquitously expressed in various tissues and binds to multiple downstream transcripts, interfering with physiological and pathological processes such as tumor growth, body metabolism, cardiovascular homeostasis, and central nervous system damage [2].

In glioblastoma cells, knockdown of Ptbp1 promotes neural differentiation via the UNC5B receptor, suppressing cancer cell proliferation both in vitro and in vivo [1]. In glioma stem cells, hyperlactylation of Ptbp1 at K436 supports glioma progression and stem cell maintenance by enhancing RNA-binding capacity and facilitating PFKFB4 mRNA stabilization, thus increasing glycolysis [3]. In the context of oncogene-induced senescence, inhibition of Ptbp1 can prevent the pro-tumorigenic effects of the senescence-associated secretory phenotype (SASP) [4]. In macrophages, the METTL3/MALAT1/PTBP1/USP8/TAK1 axis promotes pyroptosis and M1 polarization, contributing to liver fibrosis [5]. In intrahepatic cholangiocarcinoma, circRNA MBOAT2 stabilizes Ptbp1 to facilitate FASN mRNA cytoplasmic export, promoting cancer progression [6]. In dilated cardiomyopathy, lncRNA DCRT binds to Ptbp1 to prevent NDUFS2 alternative splicing, protecting against the disease [7].

In summary, Ptbp1 is crucial for RNA processing and has far-reaching impacts on multiple biological processes and diseases. Loss-of-function studies, such as knockdown experiments in cell lines and potential KO/CKO mouse models (implied by the cell-based functional studies), have revealed its role in cancer (including glioblastoma, glioma, and cholangiocarcinoma), inflammation-related fibrosis, and heart disease. These findings provide insights into disease mechanisms and potential therapeutic targets related to Ptbp1.

References:

1. Wang, Kankai, Pan, Sishi, Zhao, Peiqi, Zhuge, Qichuan, Yang, Jianjing. 2022. PTBP1 knockdown promotes neural differentiation of glioblastoma cells through UNC5B receptor. In Theranostics, 12, 3847-3861. doi:10.7150/thno.71100. https://pubmed.ncbi.nlm.nih.gov/35664063/

2. Yu, Qi, Wu, Tongtong, Xu, Wenhong, Li, Meiying, Chi, Guangfan. 2023. PTBP1 as a potential regulator of disease. In Molecular and cellular biochemistry, 479, 2875-2894. doi:10.1007/s11010-023-04905-x. https://pubmed.ncbi.nlm.nih.gov/38129625/

3. Zhou, Zijian, Yin, Xianyong, Sun, Hao, Wang, Shan, Xin, Tao. . PTBP1 Lactylation Promotes Glioma Stem Cell Maintenance through PFKFB4-Driven Glycolysis. In Cancer research, 85, 739-757. doi:10.1158/0008-5472.CAN-24-1412. https://pubmed.ncbi.nlm.nih.gov/39570804/

4. Georgilis, Athena, Klotz, Sabrina, Hanley, Christopher J, Zender, Lars, Gil, Jesús. . PTBP1-Mediated Alternative Splicing Regulates the Inflammatory Secretome and the Pro-tumorigenic Effects of Senescent Cells. In Cancer cell, 34, 85-102.e9. doi:10.1016/j.ccell.2018.06.007. https://pubmed.ncbi.nlm.nih.gov/29990503/

5. Shu, Bo, Zhou, Ying-Xia, Li, Hao, He, Chao, Yang, Xin. 2021. The METTL3/MALAT1/PTBP1/USP8/TAK1 axis promotes pyroptosis and M1 polarization of macrophages and contributes to liver fibrosis. In Cell death discovery, 7, 368. doi:10.1038/s41420-021-00756-x. https://pubmed.ncbi.nlm.nih.gov/34839365/

6. Yu, Xiaopeng, Tong, Huanjun, Chen, Jialu, Wang, Shouhua, Tang, Zhaohui. 2023. CircRNA MBOAT2 promotes intrahepatic cholangiocarcinoma progression and lipid metabolism reprogramming by stabilizing PTBP1 to facilitate FASN mRNA cytoplasmic export. In Cell death & disease, 14, 20. doi:10.1038/s41419-022-05540-y. https://pubmed.ncbi.nlm.nih.gov/36635270/

7. Du, Hengzhi, Zhao, Yanru, Wen, Jianpei, Wang, Dao Wen, Chen, Chen. 2024. LncRNA DCRT Protects Against Dilated Cardiomyopathy by Preventing NDUFS2 Alternative Splicing by Binding to PTBP1. In Circulation, 150, 1030-1049. doi:10.1161/CIRCULATIONAHA.123.067861. https://pubmed.ncbi.nlm.nih.gov/38841852/