The 22 item MDASI-BT demonstrated validity and reliability in patients with PBT. This instrument can be used to identify symptom occurrence throughout the disease trajectory and to evaluate interventions designed for symptom management.
The Tup1-Ssn6 corepressor complex in Saccharomyces cerevisiae represses the transcription of a diverse set of genes. Chromatin is an important component of Tup1-Ssn6-mediated repression. Tup1 binds to underacetylated histone tails and requires multiple histone deacetylases (HDACs) for its repressive functions. Here, we describe physical interactions of the corepressor complex with the class I HDACs Rpd3, Hos2, and Hos1. In contrast, no in vivo interaction was observed between Tup-Ssn6 and Hda1, a class II HDAC. We demonstrate that Rpd3 interacts with both Tup1 and Ssn6. Rpd3 and Hos2 interact with Ssn6 independently of Tup1 via distinct tetratricopeptide domains within Ssn6, suggesting that these two HDACs may contact the corepressor at the same time.The Tup1-Ssn6 corepressor complex mediates repression of a large and diverse set of genes in Saccharomyces cerevisiae (reviewed in Ref. 1). Examples of gene classes regulated by this co-repressor complex are genes that are repressed by glucose (e.g. SUC2), genes that respond to hypoxia (e.g. ANB1), genes induced by DNA damage (e.g. RNR2), and cell type-specific genes (e.g. STE6). Tup1-Ssn6 does not bind directly to DNA but is recruited to target genes by interactions with DNA-bound repressor proteins. The molecular mechanism by which Tup1-Ssn6 inhibits transcription is not fully understood, but Tup1-Ssn6 probably uses both interactions with chromatin and interactions with the general transcription machinery to achieve repression. Many subunits of the mediator complex that is associated with the C-terminal domain of the largest subunit of RNA polymerase II interact both genetically and physically with Tup1-Ssn6 (2-5).Tup1-Ssn6 also directly interacts with histones and influences the organization of chromatin. Certain repressed genes under Tup1-Ssn6 control are packaged into highly positioned nucleosomes during repression (6 -9). Tup1 binds preferentially to underacetylated H3 and H4 amino-terminal histone tails in vitro, and combined mutation of the H3 and H4 tails leads to a large derepression of Tup1-Ssn6-regulated genes in vivo (10, 11). Chromatin immunoprecipitation experiments indicate that Tup1 binding in vivo is associated with decreased acetylation of H3 and H4 (12-14). Accordingly, histone deacetylase activities are required for Tup1-Ssn6 repression (15, 16). Combined loss of three class I histone deacetylases, Rpd3, Hos1, and Hos2, completely abolishes Tup1-Ssn6 repression at all genes examined (15). Mutations in the class II deacetylase, Hda1, shows partial derepression of ENA1, another Tup1-Ssn6-regulated gene (16). Interactions between Tup1-Ssn6 and Rpd3, Hos2, and Hda1 have been detected using a combination of in vitro and in vivo techniques. HA 1 -Hos2 interacts with both a LexA-Ssn6 construct in vivo and a GST-Ssn6 construct in vitro. In vitro translated Hda1 interacts with GST-Tup1 in vitro. However, only Rpd3 has heretofore been shown to interact with native Tup1-Ssn6 in vivo.In this work, we demonstrate that native Tup1-Ssn6 interacts with multiple...
In the original article, the third author's name was misspelled.The online version of the original article can be found at http:// dx
Previous studies revealed that deletion of genes encoding the histone acetyltransferases GCN5, p300, or CBP results in embryonic lethality in mice. PCAF and GCN5 physically interact with p300 and CBP in vitro. To determine whether these two groups of histone acetyltransferases interact functionally in vivo, we created mice lacking one or more alleles of p300, GCN5, or PCAF. As expected, we found that mice heterozygous for any single null allele are viable. The majority of GCN5 ϩ/Ϫ p300 ϩ/Ϫ mice also survive to adulthood with no apparent abnormalities. However, ϳ25% of these mice die before birth. These embryos are developmentally stunted and exhibit increased apoptosis compared with wild-type or single GCN5 ϩ/Ϫ or p300 ϩ/Ϫ littermates at embryonic day 8.5. In contrast, no abnormalities were observed in PCAF Ϫ/Ϫ p300 ϩ/Ϫ mice. Of interest, we find that p300 protein levels vary in different mouse genetic backgrounds, which likely contributes to the incomplete penetrance of the abnormal phenotype of GCN5 ϩ/Ϫ p300 ϩ/Ϫ mice. Our data indicate that p300 cooperates specifically with GCN5 to provide essential functions during early embryogenesis. Developmental Dynamics 233:1337-1347, 2005.
1546 Background: The occurrence of symptoms has been shown to predict treatment course and survival in a number of solid tumor patients. Primary brain tumor patients are unique in the neurologic symptoms that occur. Currently, no instrument exists that measures both neurologic and cancer-related symptoms. Methods: Patients diagnosed with Primary Brain Tumors (PBT) participated in this study. Data collection tools included a patient completed demographic data sheet, an investigator completed clinician checklist, and the core M.D. Anderson Symptom Inventory to which 18 neurologic symptoms were added (M.D. Anderson Symptom Inventory-Brain Tumor Module, MDASI-BT). The study evaluated the reliability and validity of the MDASI-BT in primary brain tumor patients. Results: 201 patients participated in this study. Mean symptom severity of items as well as cluster analysis was used to reduce the number of total items to 22. Regression analysis showed more than half (56%) of the variability in symptom severity was explained by the 9 remaining brain tumor items. Factor analysis was then performed to determine the underlying constructs being evaluated by the remaining items. The 22 item MDASI-BT measures six underlying constructs including affective, cognitive, focal neurologic deficit, constitutional, generalized symptom, and a gastrointestinal related factor. The internal consistency (reliability) of the sets of items comprising the six factors and also the interference scale were .87, .82, .72, .81, .69, .67 and .91 respectively). Test-retest reliability was good in a subset of 19 patients completing the instrument at two points in time. The MDASI-BT was sensitive to disease severity based on Karnofsky performance status (KPS) based on mean symptom severity (1.7 versus 3.8, p < .001) and mean symptom interference (2.2 versus 6.1, p < .001). Conclusions: The 22 item MDASI-BT demonstrated validity and reliability in patients with PBT. This instrument can be used to describe symptom occurrence throughout the disease trajectory and to evaluate interventions designed for symptom management. [Table: see text]
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