The C-terminus of p63 contains multiple regulatory elements with different functions

The transcription factor p63 is expressed as at least six different isoforms, of which two have been assigned critical biological roles within ectodermal development and skin stem cell biology on the one hand and supervision of the genetic stability of oocytes on the other hand. These two isoforms contain a C-terminal inhibitory domain that negatively regulates their transcriptional activity. This inhibitory domain contains two individual components: one that uses an internal binding mechanism to interact with and mask the transactivation domain and one that is based on sumoylation. We have carried out an extensive alanine scanning study to identify critical regions within the inhibitory domain. These experiments show that a stretch of ~13 amino acids is crucial for the binding function. Further, investigation of transcriptional activity and the intracellular level of mutants that cannot be sumoylated suggests that sumoylation reduces the concentration of p63. We therefore propose that the inhibitory function of the C-terminal domain is in part due to direct inhibition of the transcriptional activity of the protein and in part due to indirect inhibition by controlling the concentration of p63. Keywords: p63, transcriptional regulation, auto-inhibition, sumoylatio

Structural characterization of the C-terminal domains in the p53 protein family

The identification of many homologs and paralogs of the most famous tumor suppressor, p53, has expanded its role from tumor suppression to epidermal development, neuronal development, and protection of germ cells. Of all the members in the p53 protein family, the DNA binding domain (DBD) is the most conserved domain. In contrast, the C-terminal region is diverse in sequence and composition of protein domains that include the oligomerization domain (OD), the sterile alpha motif (SAM) domain, and the transcription inhibitory domain (TID). While the function of each domain has been delineated, the SAM domain is the least functionally characterized, yet it is conserved between vertebrate and invertebrate p53. Furthermore, mutations of this domain in p63, a homolog of p53, cause defects in epidermal development in human.The diversity of the C-terminus is most apparent in two p53 like proteins in C. elegans (CEP-1) and Drosophila (Dmp53). Neither of these proteins have any domains in the C-terminus found in other p53 protein family members, yet the DBD in both proteins recognize the DNA consensus motif in vitro. Interestingly, CEP-1 and Dmp53 could only elicit an apoptotic response, but not both cell cycle arrest and apoptosis like in human. The variation of the C-terminal end by each member of the p53 protein family may account for the discrepancy between identical in vitro DNA specificity, and distinct promoter specificity in vivo. By using bioinformatics and structural determination by nuclear magnetic resonance, the domain architecture of the C-termini of CEP-1 and Dmp53 was revealed. In CEP-1, an OD and a SAM domain were identified, in which the stability of the OD depends on its interaction with the SAM domain, thus suggesting an early function for the SAM domain. In Dmp53, the OD displays an unconventional fold that requires an additional helix to stabilize the OD. Structural and biochemical investigations into the human SAM domain in p63 also reveal that the SAM domain has interactions with the OD. Mutations in the SAM domain may disrupt this interaction and cause a change in the conformation of p63 that results in its abnormal function

Determinants of quality of life in prostate cancer patients: A single institute analysis

Objective: To determine factors that influence quality of life in prostate cancer patients. Patients and methods: Patients with pathologically verified prostate cancer and treated at the National Cheng Kung University Hospital were invited to fill out the World Health Organization Quality of Life-BREF questionnaires at the outpatient clinic. We explored the determinants of quality of life including age, education, income, marital status, disease stage, and treatment modality using a mixed-effects model. Results: From January 2013 to July 2014, a total of 248 patients were investigated and 404 measurements were performed. Among them, there were 110 patients, 48 patients, and 90 patients with localized, locally advanced, and metastatic disease, respectively. After adjustment for comorbidities and other confounders, patients who were married showed a significantly higher score in the domains of physical health, social relationships including sexual satisfaction, and opportunities to obtain information and leisure activities. A higher income was associated with a higher score in physical, psychological, and environment domains. Patients with metastatic disease showed lower scores in the physical domain. Conclusion: Our data demonstrated that marital status is an important determinant of quality of life in prostate cancer patients besides other sociodemographic factors. Clinicians are advised to provide more social support recourses for patients who do not have a partner