Diverse functional networks of Tbx3 in development and disease

Abstract

The T-box transcription factor Tbx3 plays multiple roles in normal development and disease. In order to function in different tissues and on different target genes, Tbx3 binds transcription factors or other cofactors specific to temporal or spatial locations. Examining the development of the mammary gland, limbs, and heart as well as the biology of stem cells and cancer provides insights into the diverse and common functions that Tbx3 can perform. By either repressing or activating transcription of target genes in a context-dependent manner, Tbx3 is able to modulate differentiation of immature progenitor cells, control the rate of cell proliferation, and mediate cellular signaling pathways. Because the direct regulators of these cellular processes are highly context-dependent, it is essential that Tbx3 has the flexibility to regulate transcription of a large group of targets, but only become active on a small cohort of them at any given time or place. Moreover, Tbx3 must be responsive to the variety of different upstream factors that are present in different tissues. Only by understanding the network of genes, proteins, and molecules with which Tbx3 interacts can we hope to understand the role that Tbx3 plays in normal development and how its aberrant expression can lead to disease. Because of its myriad functions in disparate developmental and disease contexts, Tbx3 is an ideal candidate for a systems-based approach to genetic function and interaction.

The T-Box transcription factor 3 in development and cancer

“…It is important to note that there is a large number of tissues and organs where TBX3 is expressed but which are unaffected by UMS, suggesting that specific doses of TBX3 may be required for its functions in different tissues. This is in line with observations that the severity of the UMS phenotype correlates with the level of TBX3 deficiency (24). It is also possible that other T-box factors, such as TBX2, could compensate for TBX3 in tissues and organs unaffected by UMS.…”

“…A putative activation domain at amino acids 423-500 was also mapped and indeed TBX3 has been shown to activate Connexin43 (18) and Gata6 (19) which are both important in heart embryogenesis. Using electrophoretic mobility shift assays (EMSA) the DNA-binding region was found to be located in the N-terminus (position 105-287 (REFSEQ: accession NM 005996.3)) and a with its extensive expression pattern, TBX3 contributes to the formation of many tissues with its most well characterised roles being in heart, mammary gland and limb development (24). As mentioned earlier, haploinsufficiency of TBX3 causes the human autosomal dominant UMS which is characterised by a wide range of congenital abnormalities including malformations of the limbs, mammary gland aplasia, loss of areola and defects in the jaw, heart and genitalia (24).…”

“…It is subsequently found in distinct areas of the developing nervous system, musculoskeleton, eye, heart, kidney, lung, liver, pancreas and mammary gland (24). TBX3 is also widely expressed in a number of human foetal organs and tissues, including heart, lung, kidney, liver and spleen (13).…”

T-box 3 overexpression is associated with poor prognosis of non-small cell lung cancer

“…The expression of Tbx3 in lung tissues has previously been demonstrated (12); however, the role of Tbx3 in the pathogenesis of NSCLC requires further investigation. To the best of our knowledge, the present study evaluated the expression level of Tbx3 in NSCLC and its association with the clinicopathological characteristics of patients with NSCLC for the first time.…”

“…The expression of Tbx3 in lung tissue under normal physiological conditions has previously been established (12). However, to the best of our knowledge, the expression status of Tbx3 in patients with NSCLC has not been investigated to date.…”