ABSTRACT
The promyelocytic leukemia (PML) tumor suppressor is essential for the formation of PML nuclear bodies (NBs). PML and PML-NBs have been implicated in the regulation of growth inhibition, senescence and apoptosis. PML is activated in response to stress signals and is downregulated in certain human cancers. However, the factors mediating PML stability are incompletely understood. Here we demonstrate that a catalytically active form of the mammalian E3 ligase E6AP (HPV E6-associated protein) acts to reduce the half-life of the PML protein by promoting its degradation in the proteasome. E6AP mediates the ubiquitination of PML in an in vitro ubiquitination assay. E6AP and PML interact at physiological levels and colocalize in PML-NBs. Importantly, PML protein expression is elevated in multiple organs and cell types from E6AP null mice and in lymphoid cells is associated with increased number and intensity of PML-NBs. This PML elevation is enhanced in response to DNA damage. Our results identify E6AP as an important regulator of PML and PML-NBs.
Subject(s)
Nuclear Proteins/metabolism , Transcription Factors/metabolism , Tumor Suppressor Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Animals , Down-Regulation , Humans , Mice , Mice, Knockout , Nuclear Proteins/deficiency , Nuclear Proteins/genetics , Promyelocytic Leukemia Protein , Transcription Factors/deficiency , Transcription Factors/genetics , Tumor Suppressor Proteins/deficiency , Tumor Suppressor Proteins/geneticsABSTRACT
This study assessed the short- and long-term effect of a gender-specific group intervention for women on unsafe sexual encounters and strategies for protection against HIV/STD infection. Family planning clients (N = 360) from a high HIV seroprevalence area in New York City were randomized to an eight-session, a four-session or a control condition and followed at one, six and 12 months post-intervention. Using an intention-to-treat analysis, women who were assigned to the eight-session group had about twice the odds of reporting decreased or no unprotected vaginal and anal intercourse compared to controls at one month (OR = 1.93, 95% confidence interval [CI] = 1.07, 3.48, p = 0.03) and at 12-month follow-up (OR = 1.65, 95% CI = 0.94, 2.90, p = 0.08). Relative to controls, women assigned to the eight-session condition reported during the previous month approximately three-and-a-half (p = 0.09) and five (p < 0.01) fewer unprotected sex occasions at one- and 12-month follow-up, respectively. Women in the eight-session group also reduced the number of sex occasions at both follow-ups, and had a greater odds of first time use of an alternative protective strategy (refusal, outercourse, mutual testing) at one-month follow-up. Results for the four-session group were in the expected direction but overall were inconclusive. Thus, gender-specific interventions of sufficient intensity can promote short- and long-term sexual risk reduction among women in a family planning setting.
