NPRL2

Official Full Name

NPR2 like, GATOR1 complex subunit

Organism

Homo sapiens

GeneID

10641

Background

Enables GTPase activator activity. Involved in cellular response to amino acid starvation; negative regulation of TORC1 signaling; and negative regulation of kinase activity. Part of GATOR1 complex. Is active in lysosomal membrane. Implicated in familial focal epilepsy with variable foci 2. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

NPR2; NPR2L; TUSC4; FFEVF2;

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Detailed Information

The tumor suppressor gene NPRL2 (nitrogen permease regulator-like2), also known as tumor suppressor candidate 4 (TUSC4), is located in the human chromosome 3p21.3 region, and is widely present in various human tissues and highly conserved among biological species. Studies have found that expression in human tumor tissues (such as lung cancer, breast cancer, and kidney cancer) is significantly reduced. NPRL2 gene has biological functions involved in DNA mismatch modification, regulating cell cycle signal transduction, and inducing apoptosis. NPRL2 gene inactivation is related to the occurrence and development of many tumors.

Nprl2 Figure 1. Schematic representation of the effects of the NPRL2 overexpression. (Ma, Y., et al. 2017)

Biological Functions of NPRL2

The NPRL2 gene is highly conserved among biological species, and the homologous gene in yeast cells is called the NPR2 gene. It encodes 152 amino acids (23%) of the same protein as human NPRL2, while 97% of the NPRL2 protein in mice is the same as human. Human NPRL2 gene is expressed in many normal tissues (including heart, brain, skeletal muscle, liver, kidney, pancreas and lung, etc.). However, it is significantly reduced in human tumor tissues (such as lung, breast, nasopharyngeal, renal cell, and ovarian cancers).

Inactivation of NPRL2 gene leads to abnormal expression of relevant tumor suppressor genes, which leads to tumor induction. The possible mechanism of this process is as follows: abnormal mismatch repair system of DNA replication leads to decreased fidelity of DNA replication and genomic instability, which leads to mutation inactivation of NPRL2 gene and promotes tumor progression. The NPRL2 gene inhibits the activation of 3-phosphoinositol-dependent protein kinase 1(PDK1). PDK1 is a key regulator of cell proliferation and signal transduction. After binding with NPRL2 gene, it leads to the inactivation of downstream signaling molecule Akt and ribosomal protein S6K of PDK1, thus inhibiting cell proliferation. Inactivation of the NPRL2 gene can cause abnormal activation of PDK1, enhance the signal transduction of PDK1 downstream cells, and lead to tumorigenesis. NPRL2 gene can increase Chk1 and Chk2 kinase activity. Chk1 and Chk2 are cell-cycle checkpoint kinases that block the cell cycle and are abnormally expressed in breast, prostate, lung, and esophageal cancers. NPRL2 gene inactivation can down-regulate Chk1 and Chk2 kinase activity and cause abnormal DNA damage repair system, thereby inhibiting tumor cell apoptosis, leading to cell cycle disorders, and promote tumorigenesis.

NPRL2's Anti-Cancer Effect

Cisplatin is one of the effective anti-tumor drugs, but its drug resistance significantly affects its clinical application value. Studies have found that after the NPR2 gene is inactivated in yeast cells, the yeast cells can resist the cytotoxic effects of cisplatin, and the structure of human NPRL2 protein is very similar to that of yeast NPR2 protein. It is possible that it also has the same biological function. Restoring normal expression of NPRL2 in drug-resistant tumor cells can re-sensitize tumor cells to chemotherapy drugs. A series of studies have shown that the expression level of NPRL2 protein is higher in cisplatin-sensitive lung cancer cell lines, while NPRL2 protein is hardly expressed in cisplatin-sensitive lung cancer cell lines. Therefore, NPRL2 may also play an important role in antitumor resistance.

Oxaliplatin is a class of DNA-damaging chemotherapeutic drugs containing 1,2-diaminocyclohexane groups. It is the third generation of platinum-based anticancer drugs after cisplatin. It has been widely used in clinic and has good curative effect. Overexpression of NPRL2 in tumor cells can inhibit cell proliferation and induce apoptosis, thereby increasing the sensitivity of oxaliplatin to CRC. Studies have shown that half of the bacteriostatic concentration of oxaliplatin in human colon cancer cell line HCT116 transfected with NPRL2 is significantly lower than that of normal cells, and that NPRL2 promotes oxaliplatin sensitivity in a time-dependent manner. After NPRL2 gene transfection into colon cancer cells, the tumor cell cycle was arrested in G1 phase, which resulted in the reduction of colon cancer cells in S phase. Compared with tumor cells not transfected with NPRL2, oxaliplatin significantly inhibited the growth of colon cancer cells transfected with NPRL2.

References:

Ma, Y. , Silveri, L. , Lacava, J. , & Dokudovskaya, S. . (2017). Tumor suppressor nprl2 induces ros production and dna damage response. Scientific Reports, 7(1), 15311.
Dutchak, P. , Laxman, S. , Estill, S. , Wang, C. , Wang, Y. , & Wang, Y. , et al. (2015). Regulation of hematopoiesis and methionine homeostasis by mtorc1 inhibitor nprl2. Cell Reports, 12(3), 371-379.
Dutchak, P. A. , Estill-Terpack, S. J. , Plec, A. A. , Zhao, X. , & Tu, B. P. . (2018). Loss of a negative regulator of mtorc1 induces aerobic glycolysis and altered fiber composition in skeletal muscle. Cell Reports, 23(7), 1907-1914.

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