Revealing the Important Regulatory Role of T-Box 3 (TBX3) in Development and Disease

TBX3 functions as a transcription factor from the T-box gene family which influences cell development through gene expression control impacting cell growth and survival. TBX3 functions as a vital regulator throughout embryonic development and plays significant roles in multiple diseases including cancer and genetic disorders. TBX3 belongs to the ancient lineage of T-box transcription factors which have been preserved through evolution and functions as a fundamental regulator during the development of the heart, mammary glands as well as limbs and lungs. Mutations in human TBX3 lead to ulnar breast syndrome which presents through multiple clinical malformations of mammary and apocrine glands along with upper limb defects and other abnormalities in areola, teeth, heart and genitals.

Fig. 1 Role and regulation of TBX3 in development and disease (Khan, S., et al. 2020).

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Developmental Functions of TBX3 in Different Tissues

Limb Development

TBX3 serves as a regulatory molecule controlling both limb patterning and cellular multiplication throughout limb development. It controls the adenylate cyclase (Shh) signaling pathway while preserving ZPA function which leads to normal limb development. The protein prevents programmed cell death while supporting distal limb growth. The occurrence of Ulnar-Mammary Syndrome (UMS) with limb malformations including ulnar hypoplasia or absence results from mutations in TBX3.

Heart Development

During heart development TBX3 functions as the primary element responsible for creating the heart's conduction system. The atrioventricular node region specifically expresses this protein to prevent cardiomyocytes from maturing while keeping them in an undifferentiated state. The atrioventricular node region remains undifferentiated from working myocardium because TBX3 blocks the expression of cardiac development factors including Nkx2.5 and GATA4. The lack of TBX3 protein can create abnormal heart signal transmission and increase arrhythmia risk.

Mammary Development

This gene expression occurs during mammary placode formation to stimulate mammary epithelial cell growth. The normal development of mammary buds occurs through the regulation of Wnt and FGF signaling pathways. UMS patients who have TBX3 gene mutations develop either mammary dysplasia or complete loss of the mammary gland.

Neural Crest Cell and Nervous System Development

TBX3 regulates the movement of neural crest cells during development. This process guides melanocyte differentiation while controlling skin pigment production. When TBX3 is inactivated it results in reduced melanocyte numbers which also impacts skin pigment formation.

Reproductive System Development

TBX3 serves as a crucial factor in both the development of external genitalia and its formation regulation. Mutations in TBX3 can result in the development of abnormal or incomplete external genitalia.

Regulatory Role of TBX3 in Cancer

TBX3 functions as an oncogene in multiple cancer types while controlling cell cycle regulation as well as apoptosis escape and EMT (epithelial-mesenchymal transition).

TBX3 promotes cancer cell survival and proliferation

The protein TBX3 suppresses the activity of p14ARF and p21 tumor suppressors which control cell cycle progression through distinct p53-dependent and independent mechanisms. TBX3 allows cells to bypass p53-related growth restrictions and support cancer cell proliferation when it decreases p14ARF expression.

TBX3 functions as a critical regulator during epithelial-mesenchymal transition and the spread of cancer cells to other tissues.

During tumor metastasis cancer cells undergo EMT which involves their transformation from epithelial cells into invasive mesenchymal cells. The function of TBX3 in cancer cells involves promotion of cell movement and invasion by suppressing E-cadherin expression while increasing N-cadherin expression. Increased invasiveness and metastatic capacity have been linked to TBX3 overexpression in breast cancer as well as in melanoma and pancreatic cancer.

TBX3 Functions in Different Cancers

TBX3 as a Potential Therapeutic Target

TBX3 functions as a tumor promoter in multiple cancers which makes it a promising target for therapeutic intervention. The following are several possible therapeutic strategies:

Small molecule inhibitors: Create therapeutic agents that focus directly on TBX3 or its essential downstream signaling routes.

RNA interference (RNAi): siRNA or shRNA can suppress TBX3 expression and block cancer cell proliferation and movement.

Epigenetic regulation: Restoring TBX3 expression to baseline levels requires the use of histone deacetylase (HDAC) inhibitors and DNA methylation regulators.

Molecular Mechanism of TBX3 in Development

The molecule blocks the p14ARF-p53 pathway while simultaneously boosting cell growth and blocking programmed cell death. The Wnt/β-catenin signaling pathway becomes active to drive the development of mammary glands as well as limbs and neural crest cells. TBX3 controls Shh (Sonic Hedgehog) signaling pathways to sustain proper limb and heart development patterns. TBX3 functions to inhibit BMP signaling which supports the maintenance of cells in an undifferentiated state while promoting cardiac conduction system formation.

Medical Researchers Identify TBX3 as a Potential Crucial Target for Disease Treatment

The transcription factor TBX3 plays a vital role in embryonic development and controls the progression of limb formation along with heart development as well as mammary gland formation and the development of the nervous and reproductive systems. The protein regulates cell growth and specialization and spatial arrangement by controlling Wnt, Shh and p53 signaling pathways. When TBX3 function becomes abnormal it leads to several developmental defects such as Ulnar-Mammary Syndrome (UMS), impaired heart conduction and mammary gland development problems. Further investigations could reveal TBX3's role in development and disease and create new treatment methods.

TBX3: an Important Target in Disease Treatment

This transcription factor regulates the disease process by controlling the cell cycle together with EMT and various signaling pathways. TBX3 shows potential as a therapeutic target because of its cancer-promoting properties and targeting TBX3 in future treatments could lead to significant advances in cancer therapy.

References

1. Khan, S., et al. The roles and regulation of TBX3 in development and disease. Gene. 2020, 726: 144223.
2. Washkowitz, AS., et al.  Diverse functional networks of Tbx3 in development and disease. Wiley Interdisciplinary Reviews: Systems Biology and Medicine. 2012, 4(3): 273-283.