This gene is a member of the paired box (PAX) family of transcription factors. Members of this gene family typically encode proteins which contain a paired box domain, an octapeptide, and a paired-type homeodomain. The PAX gene family has an important role in the formation of tissues and organs during embryonic development and maintaining the normal function of some cells after birth. The PAX genes give instructions for making proteins that attach themselves to certain areas of DNA. This nuclear protein is involved in thyroid follicular cell development and expression of thyroid-specific genes. PAX8 releases the hormones important for regulating growth, brain development, and metabolism. Also functions in very early stages of kidney organogenesis, the müllerian system, and the thymus. Additionally, PAX8 is expressed in the renal excretory system, epithelial cells of the endocervix, endometrium, ovary, Fallopian tube, seminal vesicle, epididymis, pancreatic islet cells and lymphoid cells. PAX8 and other transcription factors play a role in binding to DNA and regulating the genes that drive thyroid hormone synthesis (Tg, TPO, Slc5a5 and Tshr).
PAX8 (and PAX2) is one of the important regulators of urogenital system morphogenesis. They play a role in the specification of the first renal cells of the embryo and remain essential players throughout development.
The PAX8 gene is also associated congenital hypothyroidism due to thyroid dysgenesis because of its role in growth and development of the thyroid gland. A mutation in the PAX8 gene could prevent or disrupt normal development. These mutations can affect different functions of the protein including DNA biding, gene activation, protein stability, and cooperation with the co-activator p300. PAX gene deficiencies can result in development defects called Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).
PAX8 is considered a "master regulator transcription factor". As a master regulator, it is possible that it regulates expression of genes other than thyroid-specific. Several known tumor suppressor genes like TP53 and WT1 have been identified as transcriptional targets in human astrocytoma cells. Over 90% of thyroid tumors arise from follicular thyroid cells. A fusion protein, PAX8-PPAR-γ, is implicated in some follicular thyroid carcinomas and follicular-variant papillary thyroid carcinoma. The mechanism for this transformation is not well understood, but there are sever proposed possibilities.
Inhibition of normal PPAR y function by chimeric PAX8/PPARy protein through a dominant negative effect
Activation of normal PPARy targets due to the over expression of the chimeric protein that contain all functional domains of wild-type PPAR y
Deregulation of PAX8 function
Activation of a set of genes unrelated to both wild-type PPARy and wild-type PAX8 pathways
The PAX 8 gene has some association with follicular thyroid tumors. PAX8/PPARy rearrangement account for 30-40% of conventional type follicular carcinomas and less than 5% of oncocytic carcinomas (aka Hurthle-Cell Neoplasms). Tumors expressing the PAX8/PPARy are usually present in at a young age, small in size, present in a solid/nested growth pattern and frequently involve vascular invasion. It has been observed that PAX8/PPAR y-positive tumors rarely express RAS mutations in combination. This suggests that follicular carcinomas develop in two distinct pathways either with PAX8/PPAR y or RAS.
Some whole-genome sequencing studies have shown that PAX8 also targets BRCA1 (carcinogenesis), MAPK pathways (thyroid malignancies), and Ccnb1 and Ccnb2 (cell-cycle processes). PAX8 is shown to be involved in tumor cell proliferation and differentiation, signal transduction, apoptosis, cell polarity and transport, cell motility and adhesion.
Expression of PAX8 is increased in neoplastic renal tissues, Wilms tumors, ovarian cancer and Müllerian carcinomas. For this reason, the immunodetection of PAX8 is widely used for diagnosing primary and metastatic renal tumors. Re-activation of PAX8 (or Pax2) expression has been reported in pediatric Wilms Tumors, almost all subtypes of renal cell carcinoma, nephrogenic adenomas, ovarian cancer cells, bladder, prostate, and endometrial carcinomas. The mechanism of switching on the genes is unknown. Some studies have suggested that the renal PAX genes act as pro-survival factors and allow tumor cells to resist apoptosis. Down regulation of the PAX gene expression inhibits cell growth and induces apoptosis. This could be a possible avenue for therapeutic targets in renal cancer.
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