Biomedical subjects

Elisa Garcia-Wilson

Publications and source records attributed to Elisa Garcia-Wilson.

4 recordsLinked to original sources

PubMed2006

Nucleosome dynamics.

In the 30 years since the discovery of the nucleosome, our picture of it has come into sharp focus. The recent high-resolution structures have provided a wealth of insight into the function of the nucleosome, but they are inherently static. Our current knowledge of how nucleosomes can be reconfigured dynamically is at a much earlier stage. Here, recent advances in the understanding of chromatin structure and dynamics are highlighted. The ways in which different modes of nucleosome reconfiguration are likely to influence each other are discussed, and some of the factors likely to regulate the dynamic properties of nucleosomes are considered.

Adenosine Triphosphate↗

PubMed2005

p21WAF1/CIP1 regulates the p300 sumoylation motif CRD1 through a C-terminal domain independently of cyclin/CDK binding.

Although best known for its ability to inhibit Cyclin/Cdk complexes and the replication protein PCNA, p21(WAF1/CIP1) is a multifunctional protein that interacts with many cellular binding partners, including a number of transcriptional regulators. Previously, we characterized p21 derepression of the p300 sumoylation-dependent transcriptional repression domain, CRD1. Such repression domains are at least partially dependent upon recruitment of histone deacetylase (HDAC) complexes but the mechanism through which p21 selectively disrupts CRD1 activity remains unknown. Here, we demonstrate that distinct motifs in the C-terminus of p21 are required for regulation of p300 CRD1 function and that this effect does not correlate with Cyclin or PCNA binding. Through the creation of N-terminal glutathione-s-transferase fusion proteins, which also overcome the problems of instability that result from many p21 mutations, we investigated p21 binding to HDACs. Although p21 binds both Class I and Class II HDACs in vitro, only weak association with HDAC1 and 2 is seen in cells. Mutation of the p21 PCNA binding domain significantly increases this interaction suggesting that binding is mutually exclusive and only naturally occurs under certain conditions. Binding of HDACs also failed to correlate with CRD1 inducibility, suggesting that p21 targets other transcriptional repression complexes to mediate this effect.

Amino Acid Motifs↗

PubMed2003

P300 transcriptional repression is mediated by SUMO modification.

p300 and CREB binding protein can both activate and repress transcription. Here, we locate the CRD1 transcriptional repression domain between residues 1017 and 1029 of p300. This region contains two copies of the sequence psiKxE that are modified by the ubiquitin-like protein SUMO-1. Mutations that reduce SUMO modification increase p300-mediated transcriptional activity and expression of a SUMO-specific protease or catalytically inactive Ubc9 relieved repression, demonstrating that p300 repression was mediated by SUMO conjugation. SUMO-modified CRD1 domain bound HDAC6 in vitro, and p300 repression was relieved by histone deacetylase inhibition and siRNA-mediated ablation of HDAC6 expression. These results reveal a mechanism controlling p300 function and suggest that SUMO-dependent repression is mediated by recruitment of HDAC6.

Amino Acid Sequence↗

PubMedDate not supplied

Induction of transcription through the p300 CRD1 motif by p21WAF1/CIP1 is core promoter specific and cyclin dependent kinase independent.

The tumor suppressors p300 and CREB-binding protein (CBP) are both multifunctional transcriptional coactivators. We have previously found that the cyclin dependent kinase (CDK) inhibitor p21(WAF1/CIP1) can stimulate transactivation by p300 and CBP through inhibiting transcriptional repression by a discrete domain within these proteins termed CRD1. Given the large number of p300/CBP associated functions, it is unlikely that p21 regulates the expression of every gene under their control, however. Here we have investigated the factors that help determine this specificity. We have discovered that while CRD1 can repress the activity of p300 at multiple promoters, induction of transcription by p21 though this motif is highly variable. Analysis of this effect revealed that p21 inducibility is determined by sequences flanking the TATA box. Significantly, p21 regulation of CRD1 domain function is independent of Cyclin /CDK inhibition suggesting a novel function of this protein. p21 does not interact directly with the CRD1 motif, however. These results give further insight into how regulators of cell growth and tumorigenesis, such as p21, can specifically target and induce the expression of select groups of genes.

Amino Acid Motifs↗