Identification of a novel K311 ubiquitination site critical for androgen receptor transcriptional activity

The androgen receptor (AR) is the main driver of prostate cancer (PC) development and progression, and the primary therapeutic target in PC. To date, two functional ubiquitination sites have been identified on AR, both located in its C-terminal ligand binding domain (LBD). Recent reports highlight the emergence of AR splice variants lacking the LBD that can arise during disease progression and contribute to castrate resistance. Here, we report a novel N-terminal ubiquitination site at lysine 311. Ubiquitination of this site plays a role in AR stability and is critical for its transcriptional activity. Inactivation of this site causes AR to accumulate on chromatin and inactivates its transcriptional function as a consequence of inability to bind to p300. Additionally, mutation at lysine 311 affects cellular transcriptome altering the expression of genes involved in chromatin organization, signaling, adhesion, motility, development and metabolism. Even though this site is present in clinically relevant AR-variants it can only be ubiquitinated in cells when AR retains LBD suggesting a role for AR C-terminus in E2/E3 substrate recognition. We report that as a consequence AR variants lacking the LBD cannot be ubiquitinated in the cellular environment and their protein turnover must be regulated via an alternate pathway

Analysis of aspects of quality of life in teachers' voice after discharged: longitudinal study

PURPOSE: To evaluate the long-term effects of voice therapy on the life quality of teachers who were discharged or abandoned the voice therapy for dysphonia. METHODS: This was a longitudinal study based on analysis of assessments with teachers of municipal schools in Belo Horizonte, who were referred to voice therapy and were discharged or abandoned the speech-language therapy for more than six months. A total of 33 teachers in the discharged group and 20 teachers in the abandoned group were contacted by phone and invited to participate in the study by answering the Voice activity and participation profile, which was forwarded to the researchers and sent via letter. RESULTS: At the moment of the pre speech therapy, the discharged and abandoned groups were homogeneous, except in relation to daily communication parameter. Comparing the discharged group in the pre and post speech-language therapy, it was showed improvements in social communication parameter as well as in the total score. The discharged group presented worsening in self-perception parameter when comparing the average values in the post therapy and current moments, and the group abandoned presented worsening in work, social communication and total score when comparing to the average values in the pre therapy and current moments. The discharged and abandoned groups differ in the present moment in all investigated parameters. CONCLUSION: Speech-language therapy for dysphonia have long term positive effects on life quality and voice of teachers who were soon discharged from the therapy and in a period of two years on average. Teachers who have abandoned treatment and did not obtain improvement in the voice showed negative impact in life quality and voice in a time of 2 years and 2 months on average