KHSRP

Official Full Name

KH-type splicing regulatory protein

Organism

Homo sapiens

GeneID

8570

Background

The KHSRP gene encodes a multifunctional RNA-binding protein implicated in a variety of cellular processes, including transcription, alternative pre-mRNA splicing, and mRNA localization (Min et al., 1997 [PubMed 9136930]; Gherzi et al., 2004 [PubMed 15175153]).[supplied by OMIM, Apr 2010]

Synonyms

p75; FBP2; KSRP; FUBP2;

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Detailed Information

KHSRP, also known as FUSE binding protein 2 (FBP2), is a member of the FBP family. The FBP family includes three members of the FBP1, FBP2 and FBP action inhibitors (FIR). The FBP family was originally identified as a family of proteins that control mRNA degradation. KHSRP is a multifunctional RNA-binding protein involved in many processes of transcriptional level and post-transcriptional gene expression control. In human chondrocytes, KHSRP has also been shown to be essential for post-transcriptional regulation of iN0S (Nitric oxide synthase) expression, which in turn can affect p38MAPK (mitogen-activated protein kinase), NF-KB (nuclear factor-kappa B) and JAK2-STAT-1 a signaling pathways, thereby mediating differences Physiological effects. Moreover, KHSRP can also promote the degradation of p-catenin mRNA to regulate the transcription of some multifunctional genes involved in cell proliferation and differentiation, which can be blocked by the PI3K-AKT (phosphatidylinositol 3' -kinase) signaling pathway. KHSRP also negatively regulates the Wnt/p-catenin signaling pathway and plays an important role in embryonic development. Trabucchi and his colleagues also provide strong evidence that KHSRP can regulate the maturation of a subset of miRNAs that play different roles in cell proliferation, apoptosis, and differentiation. In addition, KHSRP can be used as a necessary factor to target AU-rich mRNA to exogenous degradation. KHSRP can bind to a complex composed of exosomes, which mediates the rapid decline of mRNA.

In miRNA maturation, the KHSRP protein is a component of the Drosha and Dicer complexes and regulates the biogenesis of miRNA subsets. KHSRP is involved in the maturation of a range of miRNAs including let-7f, miR-21, miR-98, miR-27, miR-196a and miR-26a. KHSRP plays a role in tumorigenesis of small cell lung cancer. KHSRP protein levels were significantly increased in small cell lung cancer (SCLC) tumor tissues compared to normal lung tissue. In addition, KHSRP protein levels are closely related to the T stage of SCLC patients. In vitro, knockdown of the KHSRP gene inhibits cell proliferation and increases apoptosis, but has no effect on cell migration and invasion. Down-regulation of the KHSRP gene inhibits tumor growth in vivo. Further analysis indicated that KHSRP is involved in mR-26a maturation and inhibits the expression of PTEN (phosphatase and tensin homolog) in SCLC cells. Taken together, these findings suggest that KHSRP plays an important role in SCLC tumorigenesis and may be a potential new therapeutic target for SCLC therapy.

Impairing the function of KHSRP and p72 (Ddx17) resulted in a significant decrease in Ago2 (Argonaute 2) protein in several transformed human cell lines. P72 and KHSRP regulate Ago2 after transcription. Some data support the view that the reduction in Ago2 protein levels is most likely the result of a reduction in large amounts of miRNA in cells due to insufficient miRNA processing. The p72/KHSRP-mediated regulatory mechanism targets unloaded Ago2, which are less likely to affect the number of Ago2 complexes associated with small RNAs.

The miR-27b-3p is a component of the TGF-β (transforming growth factor b) signaling pathway that contributes to development of the EMT process through KHSRP silencing. The miR-27b-3p-mediated silencing of the single-strand RNA binding protein KHSRP is required for transforming growth factor b (TGF-β)-induced EMT in mammary gland cells. Sustained KHSRP expression limits TGF-β-dependent induction of EMT factors and cell migration, whereas its knockdown in untreated cells mimics TGF-β-induced EMT. KHSRP controls levels of mature miR-192-5p, a microRNA that targets a group of EMT (epithelial–mesenchymal transition) factors, and alternative splicing of a cohort of premRNAs related to cell adhesion and motility including Cd44 and Fgfr2. KHSRP belongs to a ribonucleoprotein complex that includes hnRNPA1, and the two proteins cooperate in promoting epithelial-type exon usage of select pre-mRNAs. Thus, TGF-β-induced KHSRP silencing is central in a pathway leading to gene-expression changes that contribute to the cellular changes linked to EMT.

References:

Shi S, et al. KHSRP Participates in Manganese-Induced Neurotoxicity in Rat Striatum and PC12 Cells. Journal of Molecular Neuroscience, 2015, 55(2):454-465.
Puppo M, et al. miRNA-Mediated KHSRP Silencing Rewires Distinct Post-transcriptional Programs during TGF-β-Induced Epithelial-to-Mesenchymal Transition. Cell Reports, 2016, 16(4):967-978.
Tong L, et al. KH-type splicing regulatory protein (KHSRP) contributes to tumorigenesis by promoting miR-26a maturation in small cell lung cancer. Molecular and Cellular Biochemistry, 2016, 422(1-2):61-74.
Jorge B, et al. Label-Free Protein-RNA Interactome Analysis Identifies Khsrp Signaling Downstream of the p38/Mk2 Kinase Complex as a Critical Modulator of Cell Cycle Progression. PLOS ONE, 2015, 10(5):e0125745-.

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