Inpp1-KO Mouse

Inpp1, known as inositol polyphosphate-1-phosphatase, is an enzyme involved in inositol phosphate recycling and lipid metabolism. It catalyzes the hydrolysis of inositol 1,3,4-trisphosphate and inositol 1,4-bisphosphate, key molecules in the phosphoinositide metabolic and signaling pathways [1,3]. It is also involved in the phospholipase C signaling system, which has been postulated as a target for lithium in manic-depressive illness [4].

In cancer research, Inpp1 expression was up-regulated in cervical cancer (CC) tissues compared to adjacent normal tissues. Overexpression promoted and knockdown suppressed cell viability, migration/invasion, and epithelial-mesenchymal transition (EMT) in CC cells. miR-27a was found to up-regulate Inpp1, contributing to tumorigenic activities in CC [1]. In colorectal cancer, its transcription was upregulated in most tumors [3]. Also, high Inpp1 expression in aggressive human cancer cells and primary high-grade human tumors was reported. Inactivation of Inpp1 reduced glycolytic intermediates used in lysophosphatidic acid synthesis, impairing cancer cell motility, invasiveness, and tumorigenicity [6]. In bipolar disorder patients, genetic variability at Inpp1 was associated with suicidal behavior. Specific genotypes and haplotypes of Inpp1 were more frequent in suicide attempters compared to non-attempters [2]. Additionally, Inpp1 gene variants were associated with lithium response in bipolar disorder patients [5].

In summary, Inpp1 is crucial in inositol phosphate recycling and lipid metabolism, and plays a role in phosphoinositide signaling. Its dysregulation is linked to cancer progression, including cervical and colorectal cancer, and has implications in bipolar disorder-related suicidal behavior and lithium response. Research on Inpp1, including through gene-knockout models (although not directly described in the references), could further elucidate its role in these disease processes, potentially providing new therapeutic targets and biomarkers.

References:

1. Li, Pu, Zhang, Qiaoge, Tang, Hua. 2019. INPP1 up-regulation by miR-27a contributes to the growth, migration and invasion of human cervical cancer. In Journal of cellular and molecular medicine, 23, 7709-7716. doi:10.1111/jcmm.14644. https://pubmed.ncbi.nlm.nih.gov/31557403/

2. Jiménez, E, Arias, B, Mitjans, M, Vieta, E, Benabarre, A. 2013. Genetic variability at IMPA2, INPP1 and GSK3β increases the risk of suicidal behavior in bipolar patients. In European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 23, 1452-62. doi:10.1016/j.euroneuro.2013.01.007. https://pubmed.ncbi.nlm.nih.gov/23453640/

3. Li, S R, Gyselman, V G, Lalude, O, Dorudi, S, Bustin, S A. . Transcription of the inositol polyphosphate 1-phosphatase gene (INPP1) is upregulated in human colorectal cancer. In Molecular carcinogenesis, 27, 322-9. doi:. https://pubmed.ncbi.nlm.nih.gov/10747296/

4. Løvlie, R, Gulbrandsen, A K, Molven, A, Steen, V M. . Genomic structure and sequence analysis of a human inositol polyphosphate 1-phosphatase gene (INPP1). In Pharmacogenetics, 9, 517-28. doi:. https://pubmed.ncbi.nlm.nih.gov/10780272/

5. Mitjans, Marina, Arias, Bárbara, Jiménez, Esther, Vieta, Eduard, Benabarre, Antoni. . Exploring Genetic Variability at PI, GSK3, HPA, and Glutamatergic Pathways in Lithium Response: Association With IMPA2, INPP1, and GSK3B Genes. In Journal of clinical psychopharmacology, 35, 600-4. doi:10.1097/JCP.0000000000000382. https://pubmed.ncbi.nlm.nih.gov/26267417/

6. Benjamin, Daniel I, Louie, Sharon M, Mulvihill, Melinda M, Ng, Shu-Wing, Nomura, Daniel K. 2014. Inositol phosphate recycling regulates glycolytic and lipid metabolism that drives cancer aggressiveness. In ACS chemical biology, 9, 1340-50. doi:10.1021/cb5001907. https://pubmed.ncbi.nlm.nih.gov/24738946/