Table 1.

Systemic, cellular and molecular manifestations of Fus1 decrease/loss/increase in normal and tumor tissues.

Type of tumor or normal tissue	Systemic and molecular effects of Fus1 loss/overexpression	Reference
3p21.3-deficient lung cancer cells H1299 and A549. (Fus1 is lost as the part of 3p21.3 deletion)	Overexpression of FUS1/TUSC2 transgene suppresses proliferation, blocks G1/S or G2/M transition, and increases doubling time Intratumoral adenoviral delivery of the FUS1/TUSC2 transgene suppressed growth of tumor xenografts and inhibited experimental lung metastases in nu/nu mice	[45, 46]
Human white blood cells, human keratinocyte cell line HaCaT, human bronchial epithelial cell line BEAS-2B, human breast cancer cell lines MDA-MB231, MB468 and MT-1, a human glioblastoma cell line U87, and a mouse breast cancer cell line 4T1. All cancer cells have lower (TUSC2 expression is lower in all cancer cells than in all normal cells in the study)	Increase of Fus1/Tusc2 mRNA expression after sequestration of miRNAs by TUSC2P inhibits cell proliferation, survival, migration, invasion, colony formation and stimulates tumor cell death	[61]
Human NSCLC cell lines A549, H1299, H358, H226, H322, H460, normal human lung fibroblast cell line WI-38. (TUSC2 expression is lower in all cancer cells than in a normal cell line)	Myristoylation-deficient FUS1/TUSC2 loses its abilities to induce apoptosis and suppress tumor cell proliferation in vitro and promotes tumor growth and metastases in vivo	[53]
Murine osteoclasts from bone marrow. Normal Tusc2 levels.	Overexpression of Tusc2 positively regulates osteoclast differentiation induced by RANKL. Tusc2 induces activation of Ca2+-dependent RANKL-mediated NF-κB and CaMKIV/CREB signaling cascades.	[71]
Human NSCLC cell lines A549 and H1299, normal human lung fibroblast 32D P210 cells. (TUSC2 expression is lower in all cancer cells than in a normal cell line)	Deletion of 83-110 aa at the FUS1/TUSC2 C-terminus leads to the loss of its ability to inhibit tyrosine kinase c-Abl	[98]
Human NSCLC cell lines H1299, H460, A549, H322 and normal human bronchial epithelial cells HBEC. (TUSC2 expression is lower in all cancer cells than in a normal cell line)	Co-expression of FUS1/TUSC2 and p53 synergistically increased apoptosis associated with down-regulation of MDM2 and activation of Apaf/caspase-3	[113]
Anaplastic thyroid cancer cell line 8505 C and papillary thyroid cancer cell line TPC-1 (Fus1 level is decreased)	Overexpression of FUS1/TUSC2 increases levels of Smac/Diablo, suppressor of IAPs blocking caspase- and cytochrome c-mediated apoptosis	[115]
Cell-free (Protein Chip array and SELDI-TOF mass spectrometry)	Direct interaction between PDZ domains of FUS1/TUSC2 and Apaf	[116]
Fus1 KO mouse model (Fus1 is deleted in all tissues)	Increased frequencies of lupus-like autoimmune conditions (vasculitis, glomerulonephritis, anemia, circulating autoantibodies) and spontaneous vascular tumors, defective NK cell maturation in Fus1 KO mice completely rescued by in vivo injections of IL-15 expressing plasmid. Increased susceptibility to irradiation, enhanced response to A. baumanii infection, premature aging, hearing loss, and olfactory and spatial memory impairments.	[21–23, 48–50]
Gastrointestinal epithelial cells from irradiated Fus1 KO mice (Fus1 is deleted)	After in vivo irradiation, epithelial cells demonstrated accelerated cell cycle arrest, aberrant mitosis, lack of proper DNA repair (mitotic catastrophe), early activation of p53, inadequate cellular antioxidant defenses, defective redox homeostasism and death of gastrointestinal crypt cells. IR sensitivity in Fus1 KO cells could be alleviated by antioxidant treatment with Pyridoxamine.	[48, 49]
Activated mouse CD4+ T cells (Fus1 is deleted), human tumor cells (Fus1 is silenced)	Deletion or silencing of Fus1/Tusc2 accelerates cell proliferation	[24, 129]
Fus1 KO CD4+ T cells, mouse embryonic fibroblasts, kidney epithelial cells (Fus1 is deleted)	Loss of Fus1 altered Ca2+ signaling including mitochondrial Ca2+ accumulation during cytosolic Ca2+ rises, which led to hyperactivation of basal NFAT/NFkB and decreased NFAT/NFkB activation during Ca2+ elevations induced by cell stimulation	[24, 25, 23]
Lung tissues and BALF cells from Fus1 KO mice infected with A. Baumanii (Fus1 is deleted)	Early recruitment of lymphocytes to infection site, early activation of anti-bacterial pathways, (PI3K/Akt/mTOR pathways activation, PTEN downregulation), increased mitochondrial membrane potential and UCP2 (UnCoupled Protein 2) expression	[21]
Peritoneal granulocytes from Fus1/Tusc2 KO mice (Fus1 is deleted)	After intraperitoneal injection of asbestos, infiltrating cells demonstrate signatures of enhanced genotoxic stress (elevated γH2AX, DNA damage response molecule, and phosphorylated pro-inflammatory NFκB and ERK1/2)	[70]
Gastrointestinal epithelial cells from Fus1/Tusc2 KO mice (Fus1 is deleted)	After in vivo irradiation, epithelial cells demonstrated accelerated cell cycle arrest, aberrant mitosis, lack of proper DNA repair (mitotic catastrophe), early activation of p53, and death of gastrointestinal crypt cells	[49]
Head-and-neck cancer cells JHU012 (Fus1 is decreased), splenocytes, cochlear cells, epithelial cells from Fus1 KO mice (Fus1 is deleted)	Increased ROS production, up-regulation of antioxidant defense proteins (Prdx1) at steady-state, age-dependent decrease in the expression of Sod2 and Prdx1	[24, 50, 70]
Primary mouse embryonic fibroblasts and immortalized mouse kidney epithelial cells from Fus1 KO mice (Fus1 is deleted)	Defects in respiration (significantly decreased maximal mitochondrial respiration and respiratory reserve capacity)	[23]
Cochlear cells from Fus1 KO mice (Fus1 is deleted)	Pathological alterations in antioxidant (AO) and nutrient and energy sensing pathways (mTOR and PTEN/AKT) and down-regulation of PINK1, a sensor of mitochondrial quality control occur in cochleae of young Fus1 KO mice before major hearing loss. Short-term anti-oxidant treatment corrected these pathological molecular changes and delayed hearing loss.	[50]