Rcc1-KO Mouse

RCC1, short for regulator of chromosome condensation 1, is the sole known guanine nucleotide exchange factor of Ran, a nuclear Ras-like G protein. It binds to chromatin and works with Ran to establish a RanGTP concentration gradient, participating in crucial cell physiological activities such as nuclear envelope formation, spindle assembly, and nucleocytoplasmic transport, and is essential for cell cycle regulation [2,4,6].

In glioblastoma stem cells, disruption of the CK2-PRMT6-RCC1 signaling axis, where PRMT6 methylates RCC1, leads to mitosis defects, suggesting RCC1's role in glioblastoma malignancy [1]. In pancreatic ductal adenocarcinoma, RCC1 RNA expression is elevated, and its silencing by RNAi or CRISPR-Cas9 knockout reduces cell proliferation, migration, and clonogenicity, while enhancing apoptosis and altering cell cycle progression. It also disrupts subcellular Ran localization and the Ran gradient, and in vivo, knockout cells show reduced tumor growth potential [3]. In acute myeloid leukemia, targeting the HDAC2/c-Myc/RCC1 axis with Chidamide and Cladribine leads to cell cycle arrest and apoptosis [5]. In clear cell renal cell carcinoma, RCC1 is upregulated, promotes cell cycle progression, suppresses apoptosis, and binds to and regulates EZH2 protein stability at the post-transcriptional level through the ubiquitin-proteasome pathway [7].

In conclusion, RCC1 is vital for multiple cell cycle-related functions. Model-based research, especially gene knockout studies in relevant cancer types like glioblastoma, pancreatic, and renal cell carcinomas, as well as acute myeloid leukemia, has revealed its significant roles in tumorigenesis, cell cycle regulation, and response to therapies. These findings contribute to understanding the underlying mechanisms of these diseases and may offer potential therapeutic targets.

References:

1. Huang, Tianzhi, Yang, Yongyong, Song, Xiao, Hu, Bo, Cheng, Shi-Yuan. 2021. PRMT6 methylation of RCC1 regulates mitosis, tumorigenicity, and radiation response of glioblastoma stem cells. In Molecular cell, 81, 1276-1291.e9. doi:10.1016/j.molcel.2021.01.015. https://pubmed.ncbi.nlm.nih.gov/33539787/

2. Ren, Xuanqi, Jiang, Kai, Zhang, Feng. 2020. The Multifaceted Roles of RCC1 in Tumorigenesis. In Frontiers in molecular biosciences, 7, 225. doi:10.3389/fmolb.2020.00225. https://pubmed.ncbi.nlm.nih.gov/33102517/

3. Bannoura, Sahar F, Aboukameel, Amro, Khan, Husain Yar, Pasche, Boris C, Azmi, Asfar S. 2024. RCC1 regulation of subcellular protein localization via Ran GTPase drives pancreatic ductal adenocarcinoma growth. In Cancer letters, 604, 217275. doi:10.1016/j.canlet.2024.217275. https://pubmed.ncbi.nlm.nih.gov/39321913/

4. Jing, Li, Kwok, Hang Fai. . The intricate roles of RCC1 in normal cells and cancer cells. In Biochemical Society transactions, 50, 83-93. doi:10.1042/BST20210861. https://pubmed.ncbi.nlm.nih.gov/35191966/

5. Gu, Siyu, Hou, Yue, Dovat, Katarina, Song, Chunhua, Ge, Zheng. 2023. Synergistic effect of HDAC inhibitor Chidamide with Cladribine on cell cycle arrest and apoptosis by targeting HDAC2/c-Myc/RCC1 axis in acute myeloid leukemia. In Experimental hematology & oncology, 12, 23. doi:10.1186/s40164-023-00383-5. https://pubmed.ncbi.nlm.nih.gov/36849955/

6. Hadjebi, Ouadah, Casas-Terradellas, Eduard, Garcia-Gonzalo, Francesc R, Rosa, Jose Luis. 2008. The RCC1 superfamily: from genes, to function, to disease. In Biochimica et biophysica acta, 1783, 1467-79. doi:10.1016/j.bbamcr.2008.03.015. https://pubmed.ncbi.nlm.nih.gov/18442486/

7. Wu, Yunfei, Xu, Zhijie, Chen, Xiaoyi, Tian, Junjie, Jin, Baiye. 2023. RCC1 functions as a tumor facilitator in clear cell renal cell carcinoma by dysregulating cell cycle, apoptosis, and EZH2 stability. In Cancer medicine, 12, 19889-19903. doi:10.1002/cam4.6594. https://pubmed.ncbi.nlm.nih.gov/37747077/