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GT198

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Last Updated: 24 November 2020

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General | Latest Info

AUGUSTA, Ga.-When mutate, gene known for its ability to repair DNA, appears to instead cause breast cancer, scientists report. Gene GT198, whether mutated by genetics and / or environmental factors, has strong potential both as a way to diagnose Breast Cancer early and as a new treatment target, say Dr. Lan Ko, Cancer biologist in the Department of Pathology at Medical College of Georgia at AUGUSTA University and at Georgia Cancer Center at AU. Mutations of gene are know to be present in both early onset breast and ovarian Cancer. Now scientists have shown that stem, or progenitor cells, which should ultimately make healthy breast tissue, can also have GT198 mutations that prompt them to instead make perfect bed for Breast Cancer. Their studies, published in American Journal of Pathology, were do on international sampling of 254 cases of Breast Cancer in pre-and postmenopausal women. This gene mutation can be found in both blood and tumor tissue of patients, and in tissue, it's in high percentages, said Ko, study's corresponding author. We believe that once this gene is mutate, it induces Tumors to grow. GT198, which is also a coactivator of receptors for steroid hormones such as estrogen, is normally regulated by estrogen, Ko say. But once mutate, GT198 can enable tumor production without estrogen. Regardless of how many hormones you have, it's out-of-control growth, Ko says of resulting classic, rapid growth of Cancer. In cancerous breast, scientists have seen problems with various components of breast tissue but could not fully explain why they happen. Tissue, called Stroma, includes fat cells, or Adipocytes, that provide padding; fibroblasts, which make framework for tissue; Pericytes in blood vessels, which are contractile cells that help regulate blood pressure; as well as Myoepithelial cells comprising the outer layer of the ductal system through which milk flow. The new study backs up a few steps and shows that mutate GT198 also directly affects stem cells found on blood vessels that make these various components of breast tissue. This put it together, Ko say. It's new target in cancer. It's very exciting, says Dr. Nita Maihle, MCG Cancer biologist, associate Center Director for education at University's Cancer Center and study co-author. This tells you that all different types of stromal cells in breast tissue are affected by GT198 mutation because they all come from common progenitor Cell. The net effect is tumorigenic environment is filled with what Ko calls inappropriate offspring. Here is a cause-consequence relationship, she say. Next steps include pursuing therapies, including antibodies and herb-derived treatments, that target misguide progenitor cells, instead of only targeting cancerous breast tissue they produce, Ko say. We think the way to treat Breast Cancer is to target progenitor cells. We want to kill these cells that are feeding tumors rather than just killing tumor cells, which is less effective.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Materials and Methods

Alternative pre-mRNA splicing yields functionally distinct splice variants in regulating normal cell differentiation as well as cancer development. Putative tumor suppressor gene GT198, encoding Protein also know as TBPIP and Hop2, has been shown to regulate steroid hormone receptor-mediate transcription and to stimulate homologous recombination in DNA repair. Here, we have identified 6 distinct GT198 Splice variant transcripts generated by Alternative promoter usage or Alternative splicing. Various Splice variant transcripts preserve common open reading frame, which encode DNA binding domain of GT198. Splice variants act as dominant negatives to counteract wild-type GT198 activity in transcription and to abolish Rad51 Foci formation during radiation-induced DNA damage. In fallopian tube cancer, we have identified 44 point mutations in the GT198 cluster in 2 mutation hotspot sequences. Mutation hotspots coincide with regulatory sequences responsible for Alternative splicing, strongly supporting that imbalanced Alternative splicing is a select consequence of cancer. In addition, Splice variant-associate cytoplasmic expression is found in tumors carrying germline or somatic GT198 mutations. An Alter Alternative splicing pattern with increased variants is also present in lymphoblastoid cells derived from familial breast cancer patients carrying GT198 germline mutations. Furthermore, GT198 and its variants are reciprocally expressed during mouse stem cell differentiation. Constitutive expression of GT198 variant but not wild type induces tumor growth in nude mice. Our results collectively suggest that mutations in the GT198 gene deregulate Alternative splicing. Defective Alternative splicing promotes antagonizing variants and in turn induces loss of wild type in tumorigenesis. Study highlights role of Alternative splicing in tumor suppressor gene inactivation. Alternative splicing control is an integral step in pre-mRNA transcription, and more than 90 % of multiexon genes in the human genome are alternatively splice. 1 Various choices of Alternative splicing include Exon skipping, intron retention, Alternative 5 or 3 Splice site usage, and multiple promoters. 2 3 Alternative splicing is regulated by enhancing or silencing regulatory sequence elements located at introns and exons. 3 Alternative splicing choice is also controlled by promoter activity since transcription and alternative splicing are couple. 4 Splice variants often yield proteins functionally distinct from wild types in regulating normal differentiation and development. 5 in contrast, defective alternative splicing is frequently associated with disease and cancer. 6 7 For example, breast and ovarian cancer gene BRCA1 regulates homologous DNA recombination. The 8 9 Protein domain encoded by its large Exon 11 is responsible for Rad51-mediate DNA repair. 10 11 Splice variant BRCA111b, lacking large sequence in Exon 11, is abnormally overexpressed in breast cancer, resulting in potential suppression of wild-type BRCA1. 12 Consistently, germline mutations in BRCA1 Exon 11 promote expression of BRCA111b. 13 Additional germline mutations in BRCA1 have also been identify, causing aberrant splicing 14 15 or altering Alternative splicing. 16-18 Since single pre-mRNA can be processed to generate multiple functional isoforms, it is essential to analyze interrelationship between wild-type and splice variants when characterizing gene functions in cancer or disease.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

DISCUSSION

Taxol is one of the most successful chemotherapeutic drugs in the treatment of Human Cancer. It has recently been questioned whether the mechanism of action in mitotic arrest, which is ubiquitously present in all cells, is sufficient to explain tumor specificity, clinical efficacy, and side effects of taxol. In this report, we have identified the new protein target of taxol as GT198. GT198 is an oncoprotein and DNA repair factor involved in human common solid tumors. The GT198 gene carries germline mutations in breast and Ovarian Cancer families and recurrent somatic mutations in the tumor microenvironment. Mutant GT198 was identified in pericyte stem cells on capillary blood vessels inducing tumor angiogenesis. GT198 is a DNA-binding protein dimer, also stimulates DNA repair, regulates meiosis, participates in homologous DNA recombination, and activates nuclear receptor-mediate gene expression. Here we show that taxol directly bind to the DNA-binding domain of GT198 in vitro. Taxol serves as an allosteric inhibitor to block DNA binding to GT198 with IC50 of 8. 6 nM. Label taxol colocalizes with GT198 in interphase nuclei of cultured cells. Decrease GT198 expression.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Sources

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

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