Estrogen receptor α (ERα) plays an important role in the onset and progression of breast cancer, whereas p53 functions as a major tumor suppressor. We previously reported that ERα binds to p53, resulting in inhibition of transcriptional regulation by p53. Here, we report on the molecular mechanisms by which ERα suppresses p53's transactivation function. Sequential ChIP assays demonstrated that ERα represses p53-mediated transcriptional activation in human breast cancer cells by recruiting nuclear receptor corepressors (NCoR and SMRT) and histone deacetylase 1 (HDAC1). RNAi-mediated down-regulation of NCoR resulted in increased endogenous expression of the cyclin-dependent kinase (CDK)-inhibitor p21 Waf1/Cip1 (CDKN1A) gene, a prototypic transcriptional target of p53. While 17β-estradiol (E2) enhanced ERα binding to p53 and inhibited p21 transcription, antiestrogens decreased ERα recruitment and induced transcription. The effects of estrogen and antiestrogens on p21 transcription were diametrically opposite to their known effects on the conventional ERE-containing ERα target gene, pS2/TFF1. These results suggest that ERα uses dual strategies to promote abnormal cellular proliferation: enhancing the transcription of ERE-containing proproliferative genes and repressing the transcription of p53-responsive antiproliferative genes. Importantly, ERα binds to p53 and inhibits transcriptional activation by p53 in stem/progenitor cell-containing murine mammospheres, suggesting a potential role for the ER-p53 interaction in mammary tissue homeostasis and cancer formation. Furthermore, retrospective studies analyzing response to tamoxifen therapy in a subset of patients with ER-positive breast cancer expressing either wild-type or mutant p53 suggest that the presence of wild-type p53 is an important determinant of positive therapeutic response.nuclear receptor corepressor | mammary epithelial cells | mammospheres | tumor suppressor protein | tamoxifen therapy

Traumatic brain injury (TBI) is a leading cause of death and disability in people younger than 45 and is a significant public health concern. In addition to primary mechanical damage to cells and tissue, TBI involves additional molecular mechanisms of injury, termed secondary injury, that continue to evolve over hours, days, weeks, and beyond. The trajectory of recovery after TBI is highly unpredictable and in many cases results in chronic cognitive and behavioral changes. Acutely after TBI, there is an unregulated release of glutamate that cannot be buffered or cleared effectively, resulting in damaging levels of glutamate in the extracellular space. This initial loss of glutamate homeostasis may initiate additional changes in glutamate regulation. The excitatory amino acid transporters (EAATs) are expressed on both neurons and glia and are the principal mechanism for maintaining extracellular glutamate levels. Diffusion of glutamate outside the synapse due to impaired uptake may lead to increased extrasynaptic glutamate signaling, secondary injury through activation of cell death pathways, and loss of fidelity and specificity of synaptic transmission. Coordination of glutamate release and uptake is critical to regulating synaptic strength, long-term potentiation and depression, and cognitive processes. In this review, we will discuss dysregulation of extracellular glutamate and glutamate uptake in the acute stage of TBI and how failure to resolve acute disruptions in glutamate homeostatic mechanisms may play a causal role in chronic cognitive symptoms after TBI.

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Background: Nuclear receptor corepressors form complexes with histone deacetylase 3 (HDAC3). Results: Interplay of HDAC3 degradation and its complex formation with corepressors maintains free HDAC3 levels, allowing independent formation of nuclear receptor corepressor complexes. Conclusion: By controlling HDAC3 expression, N-CoR and SMRT corepressors do not interfere with their independent complex formation with HDAC3. Significance: Independent formation of nuclear receptor corepressor complexes ensures their independent biological functions.

Paramyxoviruses are a diverse family which utilizes a fusion (F) protein to enter cells via fusion of the viral lipid bilayer with a target cell membrane. Although certain regions of F are known to play critical roles in membrane fusion, the function of much of the protein remains unclear. Sequence alignment of a set of paramyxovirus F proteins and analysis utilizing Block Maker identified a region of conserved amino acid sequence in a large domain between the heptad repeats of F 1 , designated CBF 1 . We employed site-directed mutagenesis to analyze the function of completely conserved residues of CBF 1 in both the simian virus 5 (SV5) and Hendra virus F proteins. The majority of CBF 1 point mutants were deficient in homotrimer formation, proteolytic processing, and transport to the cell surface. For some SV5 F mutants, proteolytic cleavage and surface expression could be restored by expression at 30°C, and varying levels of fusion promotion were observed at this temperature. In addition, the mutant SV5 F V402A displayed a hyperfusogenic phenotype at both 30°C and 37°C, indicating this mutation allows for efficient fusion with only an extremely small amount of cleaved, active protein. The recently published prefusogenic structure of PIV5/SV5 F [Yin, H.S., et al. (2006) Nature 439, 38-44] indicates that residues within and flanking CBF 1 interact with the fusion peptide domain. Together, these data suggest that CBF 1 -fusion peptide interactions are critical for the initial folding of paramyxovirus F proteins from across this important viral family, and can also modulate subsequent membrane fusion promotion.The family Paramyxoviridae comprises many diverse members, including well-known human pathogens such as measles, mumps and respiratory syncytial virus (RSV), as well as animal pathogens like parainfluenza virus 5 (PIV5/SV5), and the newly emerged, zoonotic Hendra and Nipah viruses. Hendra virus first emerged in 1994 and caused an outbreak of severe respiratory illness near Brisbane, Australia. This resulted in the deaths of fourteen horses and two out of three humans infected, succumbing either to respiratory illness or to viral meningoencephalitis (1,2). Nipah virus was responsible for an outbreak of viral encephalitis in Malaysia in 1998, which resulted in the deaths of 105 people and the preventative destruction of over one million swine (3). Hendra and Nipah virus are classified as NIAID priority pathogens and DHHS Select Agents, and no antiviral therapies currently exist for these fatal viruses. Hendra and Nipah are grouped into the Henipavirus genus within the family, due in part to the fact that while they possess 88% homology to each other, they share less than 30% homology with the rest of the family (4,5). † This work was supported by a grant from the National Institute of Allergy and Infectious Diseases (AI-51517) to R.E.D. A.E.G. was supported in part by a predoctoral fellowship from the American Heart Association, Ohio Valley Affiliate (0415223B).* To whom correspondence should be addres...