Ubiquitin C-terminal hydrolase deubiquitinase BAP1 is an essential tumor suppressor involved in cell growth control, DNA damage response, and transcriptional regulation.
The network analysis revealed that the candidate genes identified in AR chickens play roles in networks centered to ubiquitin C (<i>UBC</i>), phosphoinositide 3-kinases (<i>PI3K</i>), and nuclear factor kappa B (<i>NF-kB</i>) complexes suggesting that the tumor regression property in AR chickens might be associated with ubiquitylation, <i>PI3K</i>, and <i>NF-kB</i> signaling pathways.
Here we describe the small molecule b-AP15 as a previously unidentified class of proteasome inhibitor that abrogates the deubiquitinating activity of the 19S regulatory particle. b-AP15 inhibited the activity of two 19S regulatory-particle-associated deubiquitinases, ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14), resulting in accumulation of polyubiquitin. b-AP15 induced tumor cell apoptosis that was insensitive to TP53 status and overexpression of the apoptosis inhibitor BCL2.
Transgenic (TG) mice expressing human chorionic gonadotropin (hCG) beta-subunit under the ubiquitin C promoter, presenting with a moderately elevated level of LH/hCG bioactivity develop multiple neoplasms secondary to the endocrine abnormalities, including mammary gland tumors after the age of 9 months.