Objective: To characterize the BET gene expression in human testis with spermatogenetic impairments; to examine BRDT protein expression in testis and semen.
Design: Prospective study.
Setting: Fertility clinic.
Patient(s): Azoospermic men (n = 120) who underwent testicular sperm extraction and who were classified as either normal spermatogenesis, mixed atrophy, spermatocyte maturation arrest, or Sertoli cells only according to their combined histologic and cytologic testicular findings and three normozoospermic men who donated sperm.
Intervention(s): Evaluation of testicular biopsies by qualitative and quantitative reverse transcriptase-polymerase chain reaction, immunohistochemical staining, and analysis of spermatozoa by immunofluorescence.
Main Outcome Measure(s): Expression of the four BET genes in testis and localization of BRDT protein in testicular tissue and ejaculated spermatozoa.
Result(s): The BRDT gene was not expressed in testicular tissue from patients with Sertoli cells only, whereas the other three genes of the BET family retained expression in all the pathologies. The BRDT protein was localized in the nuclei of spermatocytes, spermatids, and ejaculated spermatozoa. Expression of BRDT protein was almost nil in testicular tissue specimens with spermatocyte maturation arrest despite normal transcript levels.
Conclusion(s): Human BRDT expression pattern differs from mouse BRDT expression. In human, BRDT is the only BET gene expressed exclusively in testicular germ cells. Its expression in elongated spermatids and ejaculated spermatozoa raises the possibility that it is involved in unidentified additional functions.
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http://dx.doi.org/10.1016/j.fertnstert.2011.10.010 | DOI Listing |
Clin Cancer Res
January 2024
Icahn School of Medicine, Tisch Cancer Institute, New York, New York (formerly Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York).
Purpose: Endocrine-based therapy is the initial primary treatment option for hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC). However, patients eventually experience disease progression due to resistance to endocrine therapy. Molibresib (GSK525762) is a small-molecule inhibitor of bromodomain and extraterminal (BET) family proteins (BRD2, BRD3, BRD4, and BRDT).
View Article and Find Full Text PDFBioorg Chem
November 2023
Department of Pharmacy, Birla Institute of Technology and Science, Pilani-Pilani Campus, Vidya Vihar Pilani, Rajasthan 333031, India.
Bromodomain and extraterminal (BET) proteins have the ability to bind to acetylated lysine residues present in both histones and non-histone proteins. This binding is facilitated by the presence of tandem bromodomains. The regulatory role of BET proteins extends to chromatin dynamics, cellular processes, and disease progression.
View Article and Find Full Text PDFInt J Mol Sci
August 2023
Department of Pharmacology and Toxicology, Massey Cancer Center, Virginia Commonwealth University, 401 College St., Richmond, VA 23298, USA.
The bromodomain and extra-terminal domain (BET) family inhibitors are small molecules that target the dysregulated epigenetic readers, BRD2, BRD3, BRD4 and BRDT, at various transcription-related sites, including super-enhancers. BET inhibitors are currently under investigation both in pre-clinical cell culture and tumor-bearing animal models, as well as in clinical trials. However, as is the case with other chemotherapeutic modalities, the development of resistance is likely to constrain the therapeutic benefits of this strategy.
View Article and Find Full Text PDFJ Biomol Struct Dyn
September 2024
Department of Chemistry, Faculty of Science, Imam Khomeini International University, Qazvin, Iran.
We synthesized new, structurally distinct series of indeno[1,2-]pyrrol-4(1)-ones. Effective derivatives were found by in screening, and our studies revealed that compound exhibited good binding energies for inhibition of BRDT. In addition, DFT studies were carried out by means of the B3LYP/6-3lG basis set in the gas phase to investigate the conformation of protein-ligand interactions.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
July 2023
College of Veterinary Medicine, Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853.
Infertility is a heterogeneous condition, with genetic causes thought to underlie a substantial fraction of cases. Genome sequencing is becoming increasingly important for genetic diagnosis of diseases including idiopathic infertility; however, most rare or minor alleles identified in patients are variants of uncertain significance (VUS). Interpreting the functional impacts of VUS is challenging but profoundly important for clinical management and genetic counseling.
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