Paired box gene 8, also known as PAX8, is a protein which in humans is encoded by the PAX8 gene. [5]
Paired box gene 8, also known as PAX8, is a protein which in humans is encoded by the PAX8 gene. [5]
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. [6] 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. [7] 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. [8] 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. [9]
PAX8 has been shown to interact with NK2 homeobox 1. [10]
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 binding, 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 mutations are associated with various forms of cancer.
PAX8 is considered a "master regulator transcription factor". [8] 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. [8] A fusion protein, PAX8-PPAR-γ, is implicated in some follicular thyroid carcinomas and follicular-variant papillary thyroid carcinoma. [11] The mechanism for this transformation is not well understood, but there are several proposed possibilities. [12] [13] [14]
The PAX 8 gene has some association with follicular thyroid tumors. 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.
Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [5] 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.
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. [8]
Mutations in this gene have been associated with thyroid dysgenesis, thyroid follicular carcinomas and atypical follicular thyroid adenomas.
PAX8/PPARy rearrangement account for 30-40% of conventional type follicular carcinomas., [15] and less than 5% of oncocytic carcinomas (aka Hurthle-Cell Neoplasms). [16]
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. [9] Expression of PAX8 is also induced during the development of cervical cancer. [17]
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.
In evolutionary developmental biology, Paired box (Pax) genes are a family of genes coding for tissue specific transcription factors containing an N-terminal paired domain and usually a partial, or in the case of four family members, a complete homeodomain to the C-terminus. An octapeptide as well as a Pro-Ser-Thr-rich C terminus may also be present. Pax proteins are important in early animal development for the specification of specific tissues, as well as during epimorphic limb regeneration in animals capable of such.
The PAX3 gene encodes a member of the paired box or PAX family of transcription factors. The PAX family consists of nine human (PAX1-PAX9) and nine mouse (Pax1-Pax9) members arranged into four subfamilies. Human PAX3 and mouse Pax3 are present in a subfamily along with the highly homologous human PAX7 and mouse Pax7 genes. The human PAX3 gene is located in the 2q36.1 chromosomal region, and contains 10 exons within a 100 kb region.
Papillary thyroid cancer is the most common type of thyroid cancer, representing 75 percent to 85 percent of all thyroid cancer cases. It occurs more frequently in women and presents in the 20–55 year age group. It is also the predominant cancer type in children with thyroid cancer, and in patients with thyroid cancer who have had previous radiation to the head and neck. It is often well-differentiated, slow-growing, and localized, although it can metastasize.
The Von Hippel–Lindau tumor suppressor also known as pVHL is a protein that, in humans, is encoded by the VHL gene. Mutations of the VHL gene are associated with Von Hippel–Lindau disease, which is characterized by hemangioblastomas of the brain, spinal cord and retina. It is also associated with kidney and pancreatic lesions.
The sodium/iodide cotransporter, also known as the sodium/iodide symporter (NIS), is a protein that in humans is encoded by the SLC5A5 gene. It is a transmembrane glycoprotein with a molecular weight of 87 kDa and 13 transmembrane domains, which transports two sodium cations (Na+) for each iodide anion (I−) into the cell. NIS mediated uptake of iodide into follicular cells of the thyroid gland is the first step in the synthesis of thyroid hormone.
ETV6 protein is a transcription factor that in humans is encoded by the ETV6 gene. The ETV6 protein regulates the development and growth of diverse cell types, particularly those of hematological tissues. However, its gene, ETV6 frequently suffers various mutations that lead to an array of potentially lethal cancers, i.e., ETV6 is a clinically significant proto-oncogene in that it can fuse with other genes to drive the development and/or progression of certain cancers. However, ETV6 is also an anti-oncogene or tumor suppressor gene in that mutations in it that encode for a truncated and therefore inactive protein are also associated with certain types of cancers.
The steroidogenic factor 1 (SF-1) protein is a transcription factor involved in sex determination by controlling the activity of genes related to the reproductive glands or gonads and adrenal glands. This protein is encoded by the NR5A1 gene, a member of the nuclear receptor subfamily, located on the long arm of chromosome 9 at position 33.3. It was originally identified as a regulator of genes encoding cytochrome P450 steroid hydroxylases, however, further roles in endocrine function have since been discovered.
Liver X receptor alpha (LXR-alpha) is a nuclear receptor protein that in humans is encoded by the NR1H3 gene.
Paired box gene 2, also known as Pax-2, is a protein which in humans is encoded by the PAX2 gene.
SRY -box 2, also known as SOX2, is a transcription factor that is essential for maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells. Sox2 has a critical role in maintenance of embryonic and neural stem cells.
NK2 homeobox 1 (NKX2-1), also known as thyroid transcription factor 1 (TTF-1), is a protein which in humans is encoded by the NKX2-1 gene.
GATA3 is a transcription factor that in humans is encoded by the GATA3 gene. Studies in animal models and humans indicate that it controls the expression of a wide range of biologically and clinically important genes.
Paired-like homeodomain transcription factor 2 also known as pituitary homeobox 2 is a protein that in humans is encoded by the PITX2 gene.
Ras association domain-containing protein 5 is a protein that in humans is encoded by the RASSF5 or F5 gene.
Hematopoietically-expressed homeobox protein HHEX is a protein that in humans is encoded by the HHEX gene and also known as Proline Rich Homeodomain protein PRH.
Follicular thyroid cancer accounts for 15% of thyroid cancer and occurs more commonly in women over 50 years of age. Thyroglobulin (Tg) can be used as a tumor marker for well-differentiated follicular thyroid cancer. Thyroid follicular cells are the thyroid cells responsible for the production and secretion of thyroid hormones.
Forkhead box protein E1 is a protein that in humans is encoded by the FOXE1 gene.
Forkhead box protein J1 is a protein that in humans is encoded by the FOXJ1 gene. It is a member of the Forkhead/winged helix (FOX) family of transcription factors that is involved in ciliogenesis. FOXJ1 is expressed in ciliated cells of the lung, choroid plexus, reproductive tract, embryonic kidney and pre-somite embryo stage.
Mammary analogue secretory carcinoma (MASC), also termed MASCSG, is a salivary gland neoplasm. It is a secretory carcinoma which shares the microscopic pathologic features with other types of secretory carcinomas including mammary secretory carcinoma, secretory carcinoma of the skin, and salivary gland–type carcinoma of the thyroid. MASCSG was first described by Skálová et al. in 2010. The authors of this report found a chromosome translocation in certain salivary gland tumors, i.e. a (12;15)(p13;q25) fusion gene mutation. The other secretory carcinoma types carry this fusion gene.
Transmembrane protein 171 (TMEM171) is a protein that in humans is encoded by the TMEM171 gene.
A Xenopus laevis and tropicalis resource
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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