ABSTRACT
FKBPL has been implicated in processes associated with cancer, including regulation of tumor growth and angiogenesis with high levels of FKBPL prognosticating for improved patient survival. Understanding how FKBPL levels are controlled within the cell is therefore critical. We have identified a novel role for RBCK1 as an FKBPL-interacting protein, which regulates FKBPL stability at the post-translational level via ubiquitination. Both RBCK1 and FKBPL are upregulated by 17-ß-estradiol and interact within heat shock protein 90 chaperone complexes, together with estrogen receptor-α (ERα). Furthermore, FKBPL and RBCK1 associate with ERα at the promoter of the estrogen responsive gene, pS2, and regulate pS2 levels. MCF-7 clones stably overexpressing RBCK1 were shown to have reduced proliferation and increased levels of FKBPL and p21. Furthermore, these clones were resistant to tamoxifen therapy, suggesting that RBCK1 could be a predictive marker of response to endocrine therapy. RBCK1 knockdown using targeted small interfering RNA resulted in increased proliferation and increased sensitivity to tamoxifen treatment. Moreover, in support of our in vitro data, analysis of mRNA microarray data sets demonstrated that high levels of FKBPL and RBCK1 correlated with increased patient survival, whereas high RBCK1 predicted for a poor response to tamoxifen. Our findings support a role for RBCK1 in the regulation of FKBPL with important implications for estrogen receptor signaling, cell proliferation and response to endocrine therapy.
Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/drug therapy , Cyclin-Dependent Kinase Inhibitor p21/biosynthesis , Drug Resistance, Neoplasm/genetics , Immunophilins/genetics , Tamoxifen/therapeutic use , Transcription Factors/genetics , Animals , Antineoplastic Agents, Hormonal/pharmacology , Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Breast Neoplasms/mortality , COS Cells , Cell Line, Tumor , Cell Proliferation , Chlorocebus aethiops , Estradiol/metabolism , Female , Gene Expression Regulation, Neoplastic , HSP90 Heat-Shock Proteins/genetics , HSP90 Heat-Shock Proteins/metabolism , Humans , Immunophilins/biosynthesis , Neovascularization, Pathologic/genetics , Promoter Regions, Genetic/genetics , RNA Interference , RNA, Small Interfering , Receptors, Estrogen/genetics , Signal Transduction/genetics , Tacrolimus Binding Proteins , Tamoxifen/pharmacology , Transcription Factors/biosynthesis , Transcriptional Activation , Treatment Outcome , Trefoil Factor-1 , Tumor Suppressor Proteins/biosynthesis , Tumor Suppressor Proteins/genetics , Ubiquitin-Protein Ligases , UbiquitinationABSTRACT
PURPOSE: The frequency of cysts has been reported to be high in newborns, but they are rarely seen after three months of age. There has been a lack of studies describing the clinical prevalence in the premature infant after 22 weeks and less than 37 weeks gestation. The purpose of this study was to quantify and describe the clinical prevalence of palatal and alveolar cysts in premature infants as compared to full term infants. METHODS: Sixty premature infants, born at less than 37 weeks gestation, and 60 term infants, born greater than 37 weeks gestation, were examined in the first few days after birth for the presence of palatal and alveolar cysts. Alveolar cysts were further classified according to location as either maxillary or mandibular, and anterior or posterior. Information regarding birth weight, race, sex, and maternal health during pregnancy was also collected. RESULTS: The prevalence of palatal cysts in the premature infant (9%) is less than the prevalence in term infants (30%), to a statistically significant level (P < 0.004, by the Fisher's exact test). Differences between preterm and term infants were also noted in the prevalence of maxillary anterior alveolar cysts, (preterm having 27% and term 58%, P < 0.0005) and maxillary posterior alveolar cysts (preterm 2% and term 10%, P < 0.06). The prevalence of palatal and maxillary alveolar cysts was demonstrated to increase with increasing gestational age, increasing postnatal age, and increasing birth weight (by plots of cumulative percent). No significant differences were found for gender or for race. CONCLUSION: The prevalence of palatal and alveolar cysts in the premature infant is less than the prevalence in the full term infant to a statistically significant level. Palatal and maxillary alveolar cysts increase with increasing gestational age, post-natal age, and birth weight.
Subject(s)
Cysts/epidemiology , Infant, Newborn, Diseases/epidemiology , Mouth Diseases/epidemiology , Age Factors , Alveolar Process , Birth Weight , Chi-Square Distribution , Female , Gestational Age , Humans , Infant, Newborn , Infant, Premature, Diseases/epidemiology , Linear Models , Male , Mouth Mucosa/pathology , Palate , PrevalenceABSTRACT
We taught 2 4-year-old children with autism to ask questions of an adult who held a closed box with a toy inside. The treatment package (modeling, prompting, and reinforcement) was evaluated with a multiple baseline design across the three question forms during training, generalization, and follow-up evaluations. The first question form ("What's that?") produced the name of the hidden item. The second form ("Can I see it?") produced sight of it, and the third form ("Can I have it?") produced the item itself. Both children learned to ask questions about hidden objects.
