ABCC4, also known as MRP4, is an ATP-binding cassette transporter. It plays a crucial role in regulating the transport of multiple endogenous and exogenous substances, being involved in processes like cAMP homeostasis, which is essential for various biological functions [2,3,6]. It is associated with multiple signaling pathways and is important for maintaining normal cellular functions and in the context of many diseases [3,4,5,6,7,8,9,10]. Gene knockout models, such as the Abcc4-/-mice, have been valuable in studying its functions.

In megakaryopoiesis, Abcc4-/-mice show impaired proplatelet formation and polyploidization, indicating ABCC4 is required for optimal platelet formation. ABCC4 also protects megakaryocytes from 6-mercaptopurine-induced cytotoxicity as Abcc4-/-mice have a profound reduction in megakaryocytes after 6-MP treatment [1]. In the context of cytarabine-induced cytotoxicity and myelosuppression, Abcc4-null mice show enhanced cytarabine-induced hematological toxicity, suggesting ABCC4 plays a protective role against cytarabine-mediated insults in leukemic and host myeloid cells [10].

In conclusion, ABCC4 is essential for processes like megakaryopoiesis and protecting cells from certain drug-induced cytotoxicity. The use of Abcc4 gene-knockout mouse models has been instrumental in revealing its role in these processes, which has implications for understanding platelet-related disorders and chemotherapy-associated myelosuppression [1,10].

References:

1. Ranjit, Sabina, Wang, Yao, Zhu, Jingwen, Naren, Anjaparavanda P, Schuetz, John D. 2023. ABCC4 impacts megakaryopoiesis and protects megakaryocytes against 6-mercaptopurine induced cytotoxicity. In Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy, 72, 101017. doi:10.1016/j.drup.2023.101017. https://pubmed.ncbi.nlm.nih.gov/37988981/

2. Nguyen, Jenny P, Kim, Yechan, Cao, Quynh, Hirota, Jeremy A. 2021. Interactions between ABCC4/MRP4 and ABCC7/CFTR in human airway epithelial cells in lung health and disease. In The international journal of biochemistry & cell biology, 133, 105936. doi:10.1016/j.biocel.2021.105936. https://pubmed.ncbi.nlm.nih.gov/33529712/

3. Yaneff, Agustín, Sahores, Ana, Gómez, Natalia, Shayo, Carina, Davio, Carlos. . MRP4/ABCC4 As a New Therapeutic Target: Meta-Analysis to Determine cAMP Binding Sites as a Tool for Drug Design. In Current medicinal chemistry, 26, 1270-1307. doi:10.2174/0929867325666171229133259. https://pubmed.ncbi.nlm.nih.gov/29284392/

4. Kryczka, Jakub, Boncela, Joanna. 2023. Characteristics of ABCC4 and ABCG2 High Expression Subpopulations in CRC-A New Opportunity to Predict Therapy Response. In Cancers, 15, . doi:10.3390/cancers15235623. https://pubmed.ncbi.nlm.nih.gov/38067326/

5. Yu, Tao, Du, Hong, Sun, Changhai. 2022. Circ-ABCC4 contributes to prostate cancer progression and radioresistance by mediating miR-1253/SOX4 cascade. In Anti-cancer drugs, 34, 155-165. doi:10.1097/CAD.0000000000001361. https://pubmed.ncbi.nlm.nih.gov/36539368/

6. Belleville-Rolland, Tiphaine, Sassi, Yassine, Decouture, Benoit, Gaussem, Pascale, Bachelot-Loza, Christilla. 2016. MRP4 (ABCC4) as a potential pharmacologic target for cardiovascular disease. In Pharmacological research, 107, 381-389. doi:10.1016/j.phrs.2016.04.002. https://pubmed.ncbi.nlm.nih.gov/27063943/

7. Li, Le, Chao, Zheng, Peng, Hao, Wang, Zhihua, Zeng, Xing. 2024. Tumor ABCC4-mediated release of PGE2 induces CD8+ T cell dysfunction and impairs PD-1 blockade in prostate cancer. In International journal of biological sciences, 20, 4424-4437. doi:10.7150/ijbs.99716. https://pubmed.ncbi.nlm.nih.gov/39247809/

8. Chiang, Jung-Ying, Wei, Sung-Tai, Chang, Huan-Jui, Wang, Chi-Chung, Hsieh, Chia-Hung. 2024. ABCC4 suppresses glioblastoma progression and recurrence by restraining cGMP-PKG signalling. In British journal of cancer, 130, 1324-1336. doi:10.1038/s41416-024-02581-2. https://pubmed.ncbi.nlm.nih.gov/38347095/

9. Gancedo, S N, Sahores, A, Gómez, N, Davio, C A, González, B. 2024. The xenobiotic transporter ABCC4/MRP4 promotes epithelial mesenchymal transition in pancreatic cancer. In Frontiers in pharmacology, 15, 1432851. doi:10.3389/fphar.2024.1432851. https://pubmed.ncbi.nlm.nih.gov/39114357/

10. Drenberg, C D, Hu, S, Li, L, Sparreboom, A, Baker, S D. 2016. ABCC4 Is a Determinant of Cytarabine-Induced Cytotoxicity and Myelosuppression. In Clinical and translational science, 9, 51-9. doi:10.1111/cts.12366. https://pubmed.ncbi.nlm.nih.gov/26842729/