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FLASH GENE

Symbol

TSC22D3

contributors: mct/npt/pgu - updated : 17-01-2014

HGNC name	TSC22 domain family, member 3
HGNC id	3051

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	Xq22.3      Physical location : 106.956.459 - 107.019.017
Synonym name	transforming growth factor (TGF)-beta-stimulated clone 22 domain 3
	delta sleep inducing peptide, immunoreactor
	glucocorticoid-induced leucine zipper protein
Synonym symbol(s)	DIP, GILZ, DSIPI, TSC-22R, DKFZp313A1123, GILZ1, L-GILZ

DNA

TYPE	functioning gene
STRUCTURE	64.11 kb     2 Exon(s)

regulatory sequence	Promoter
text structure	FOXO3 (Forkhead box class O3) binding to the Forkhead responsive elements identified in the promoter is necessary for induction of TSC22D3 expression upon IL-2 withdrawal.

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed L-GILZ 4 - 2228 29.2 270 . in skeletal muscle tissue and in myoblasts, highly expressed in spermatogonia and primary spermatocytes 2010 20124407 Long GILZ characterized by a non-AUG translational start codon only isoform expressed in testis, and controls spermatogenesis NM_198057 3 - 2312 22.2 200 - 2010 20124407 NM_004089 2 splicing 1986 14 134 - 2010 20124407 having a different 5' end exon compared to transcript variant 1 NM_001015881 3 splicing 1781 - 77 - 2010 20124407 differing in the 5' UTR and the 5' coding region compared to variant 1

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Lymphoid/Immune lymph node       moderately   thymus       predominantly Reproductive male system testis     moderately Homo sapiens Visual eye       moderately

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / hematopoietic bone marrow       Muscular striatum skeletal   highly

cells

System Cell Pubmed Species Stage Rna symbol Lymphoid/Immune lymphocyte Homo sapiens Reproductive spermatocyte Homo sapiens Reproductive spermatogonia Homo sapiens

cell lineage
cell lines
fluid/secretion	blood

at STAGE

Text	expressed during myoblast differentiation, at a time when myotube formation became evident

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a leucine-zipper involved in homodimerization
	a C-terminal proline-rich and acidic region
	an N-glycosylation site
	several sites for threonine and serine phosphorylation

mono polymer

homomer , monomer , dimer

HOMOLOGY

interspecies	ortholog to rattus Dsipi
	ortholog to murine Tsc22d3

Homologene

FAMILY

TSC-22/Dip/Bun family

CATEGORY

transcription factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus
text	specifically expressed in the cytoplasm of proliferating spermatogonia and preleptotene spermatocytes

basic FUNCTION	being a candidate for a mediator of glucocorticoid-induced immunosuppression
	can inhibit a variety of activation-induced events
	protecting T-cells from IL2 deprivation-induced apoptosis through the inhibition of FOXO3 transcriptional activity that leads to the down-regulation of the pro-apoptotic factor BCL2L11
	in macrophages, playing a role in the anti-inflammatory and immunosuppressive effects of glucocorticoids and IL10
	in T-cells, inhibiting anti-CD3-induced NFKB1 nuclear translocation
	inhibits peroxisome proliferator-activated receptor gamma-2 (PPARG2) expression and blocks adipocyte differentiation
	functioning as a modulator of mesenchymal stem cells and overexpression of TSC22D3 shifts the balance between osteogenic and adipogenic differentiation of mesenchymal stem cells toward the osteogenic pathway
	with L-GILZ behave as modulators of myogenic differentiation, being able to inhibit myogenesis and to dampen the expression of differentiation markers such as MYHC and myogenin
	involved in the regulation of myogenesis and mediate glucocorticoids-induced anti-myogenic activity
	general inhibitor of FOXO factors acting through an original mechanism by preventing them from reaching target genes within the nucleus
	aldosterone-induced chaperone, inhibiting SGK1 ubiquitinylation and subsequent proteasome-mediated degradation, thereby prolonging its half-life and increasing its steady-state expression
	key role in controlling SGK1 protein stability and availability in specific subcellular compartments, thus selectively enhancing its regulation of a particular end point, in this case, Na+ transport
	is a novel important factor for undifferentiated spermatogonia function and spermatogenesis
	acts as an inhibitor of undifferentiated spermatogonia proliferation
	its overexpression antagonized the inhibitory effects of TNF on mesenchymal stem cell osteogenic differentiation and the mRNA and protein expression of SP7 and RUNX2, two pivotal osteogenic regulators
	essential role in mediating spermatogonial survival and spermatogenesis
	role in maintenance of the male germline and spermatogenesis
	anti-inflammatory protein first identified in T lymphocytes
	its overexpression inhibits endothelial cell adhesive function through regulation of NFKB and MAPK activity

CELLULAR PROCESS	cell life, antiapoptosis
	nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA

RNA

small molecule

protein	AP1
	NFKB1
	interacting with ANXA1 (TSC22D3 is a previously unrecognized mechanism of the anti-inflammatory effects of ANXA1)
	bind and regulate MYOD1/HDAC1 transcriptional activity, thus mediating the anti-myogenic effect of glucocorticoids
	binds RAS and inhibits RAS-dependent cell proliferation
	interacting with SGK1 (TSC22D3 and SGK1 synergize to markedly stimulate SCNN1A surface expression, by antagonizing the effects of the inhibitory components)
	is a GC effecter and mediates GC anti-inflammatory activity
	can suppress FOXO1 nuclear translocation, promotes Spermatogonia stem cell (SSC) differentiation over self-renewal, and favours germ cell survival through inhibition of BIM-dependent pro-apoptotic signals
	FKBP5 acts as an important regulator of glucocorticoid receptor (GR) activation, by decreasing ligand binding and impeding translocation of the receptor to the nucleus, while TSC22D3 mediates glucocorticoid anti-inflammatory effects

cell & other

REGULATION

induced by	glucocorticoids in lymphoid cells and monocyte/macrophage cells
		IL4 treatment in monocyte/macrophage cells
		IL10 treatment in monocyte/macrophage cells
		IL13 treatment in monocyte/macrophage cells
		IL2 deprivation in T-cells
		upon IL-2 withdrawal that protects T cells from the onset of apoptosis
		by estrogen which is important for bone homeostasis, and by sonic hedgehog (SHH) a morphogen that plays a critical role in embryogenesis

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   in synovial endothelial cells in rheumatoid arthritis

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed neuromuscular myopathy   absence of TSC22D3/L-GILZ in skeletal muscle tissue enhances muscle regeneration and glucocorticoids might be more effective in the symptomatic treatment of dystrophy immunology inflammatory   Induction of GILZ expression in endothelial cells may represent a novel therapeutic modality with the potential to inhibit inflammatory leukocyte recruitment reproduction fertility   possible target for novel therapies to intervene in male sterility

ANIMAL & CELL MODELS

Tsc22d3-2-deficient mice demonstrated a previously uncharacterized function of glucocorticoid-induced leucine zipper protein in testis development