TBX3 (T-box 3)

Note	Tbx2 and Tbx3 both belong to the Tbx2 subfamily of T-box factors (Agulnik et al., 1996). Phylogenetic analysis suggests that this subfamily originated from a single ancestral gene which was duplicated by unequal crossing over to form a two-gene cluster (Tbx2/3 and Tbx4/5) and at some point in the vertebrate lineage, duplicated again to form four separate genes with Tbx2 and Tbx4 linked on chromosome 11, and Tbx3 and Tbx5 on chromosome 5 (chromosomes 17q23 and 12q24 respectively in humans; Figure 1A) (Campbell et al., 1995; Agulnik et al., 1996; Bamshad et al., 1997). Due to the original duplication event, Tbx2 and Tbx3 form a closely related gene pair while Tbx4 and Tbx5 are more closely related to each other (Agulnik et al., 1996).
	Figure 1: A) Drawing of gene duplication. B) Drawing of TBX3 mRNA. (A) Model describing evolution of Tbx 2/3/4/5 gene family (based on Agulnick et al, 1996). (B) Schematic representation of human TBX3 mRNA depicting relative size and position of exons. In the TBX3 + 2a isoform, exon +2a is included in the mRNA through alternative splicing of the second intron.
Description	The human TBX3 gene is found on the reverse strand of chromosome 12 and spans 13.9 kb.
Transcription	Four TBX3 transcripts have been identified but only two encode for full length functional proteins viz TBX3 and TBX3 + 2a (Figure 1B). The TBX3 mRNA is 4.7 kb and contains 7 exons encoding a protein of 723 amino acids. Alternative splicing of the intronic region between exons 2 and 3 gives rise to the TBX3 + 2a transcript which contains an extra 60 bp sequence designated exon 2a leading to the production of a 743 amino acid protein (Bamshad et al., 1999). TBX3 and TBX3 + 2a isoforms are widely expressed in mouse and human tissues with TBX3 generally observed to be the dominant isoform and the ratio between the two being both tissue and species dependent (Fan et al., 2004).
Pseudogene	No pseudogenes have been identified for TBX3 to date.

Note	The TBX3 + 2a transcript yields a protein with an extra 20 amino acids in the middle of the T-box DNA binding domain, giving rise to speculation that it may affect the DNA-binding ability of the protein (Bamshad et al., 1999). While the work of Fan et al. (2004) has provided evidence supporting this hypothesis, subsequent studies have shown no functional difference between the TBX3 and TBX3 + 2a proteins (Hoogaars et al., 2008; Rodriguez et al., 2008).
	Figure 2. Schematic representation of the human TBX3 protein. The domains depicted above are: T-box, DNA binding domain (pink); R, repression domain; A, putative activation domain. The amino and carboxy termini of the protein are labelled N and C respectively.
Description	The T-box DNA binding domain is found in the N-terminal half of the TBX3 protein extending from amino acids 104 - 285 and in the TBX3 + 2a isoform, the additional 20 amino acids are inserted into the middle of the T-box at position 219 (Figure 2). TBX3 has two repression domains, one in the N-terminus and one in the C-terminus of the protein, as well as a putative activation domain located in the C-terminal end of the protein (Figure 2) (Carlson et al., 2001).
Expression	In humans, TBX3 is expressed in a number of organs, including foetal heart, liver, spleen, lung and kidney, and in adult prostate, lung, placenta, ovary, spleen, heart, kidney, testis, small intestine, adrenal gland, thyroid, breast, bladder, uterus, liver and salivary gland (Bamshad et al., 1999).
Localisation	The TBX3 protein is predominantly nuclear.
Function	TBX3 has been described to function as a transcriptional repressor and to date was shown to directly repress p14, p21, E-cadherin and phosphatase and TENsin homolog (PTEN) (Lingbeek et al., 2002; Hoogaars et al., 2008; Rodriguez et al., 2008; Burgucu et al., 2012). While in vitro assays have suggested that TBX3 is capable of transcriptional activation, it has not yet been shown to activate any physiologically relevant target genes.
Homology	Human TBX3 shares 98% amino acid identity with mouse Tbx3 and homologs have been identified in mammals, reptiles, fish and amphibians, as well as invertebrates such as tunicates (Bamshad et al., 1997).

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