Biomedical subjects

Michele K Dougherty

Publications and source records attributed to Michele K Dougherty.

5 recordsLinked to original sources

PubMed2006

Kinase suppressor of Ras1 compartmentalizes hippocampal signal transduction and subserves synaptic plasticity and memory formation.

The ERK/MAP kinase cascade is important for long-term memory formation and synaptic plasticity, with a myriad of upstream signals converging upon ERK activation. Despite this convergence of signaling, neurons routinely activate appropriate biological responses to different stimuli. Scaffolding proteins represent a mechanism to achieve compartmentalization of signaling and the appropriate targeting of ERK-dependent processes. We report that kinase suppressor of Ras (KSR1) functions biochemically in the hippocampus to scaffold the components of the ERK cascade, specifically regulating the cascade when a membrane fraction of ERK is activated via a PKC-dependent pathway but not via a cAMP/PKA-dependent pathway. Specificity of KSR1-dependent signaling also extends to specific downstream targets of ERK. Behaviorally and physiologically, we found that the absence of KSR1 leads to deficits in associative learning and theta burst stimulation-induced LTP. Our report provides novel insight into the endogenous scaffolding role of KSR1 in controlling kinase activation within the nervous system.

Adrenergic beta-Agonists↗

PubMed2005

Titan's magnetic field signature during the first Cassini encounter.

The magnetic field signature obtained by Cassini during its first close encounter with Titan on 26 October 2004 is presented and explained in terms of an advanced model. Titan was inside the saturnian magnetosphere. A magnetic field minimum before closest approach marked Cassini's entry into the magnetic ionopause layer. Cassini then left the northern and entered the southern magnetic tail lobe. The magnetic field before and after the encounter was approximately constant for approximately 20 Titan radii, but the field orientation changed exactly at the location of Titan's orbit. No evidence of an internal magnetic field at Titan was detected.

Atmosphere↗

PubMed2005

Regulation of Raf-1 by direct feedback phosphorylation.

The Raf-1 kinase is an important signaling molecule, functioning in the Ras pathway to transmit mitogenic, differentiative, and oncogenic signals to the downstream kinases MEK and ERK. Because of its integral role in cell signaling, Raf-1 activity must be precisely controlled. Previous studies have shown that phosphorylation is required for Raf-1 activation, and here, we identify six phosphorylation sites that contribute to the downregulation of Raf-1 after mitogen stimulation. Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli. The hyperphosphorylated/desensitized Raf-1 is subsequently dephosphorylated and returned to a signaling-competent state through interactions with the protein phosphatase PP2A and the prolyl isomerase Pin1. These findings elucidate a critical Raf-1 regulatory mechanism that contributes to the sensitive, temporal modulation of Ras signaling.

Animals↗

PubMed2004

Estrogen receptor expression and sensitivity to paclitaxel in breast cancer.

A retrospective analysis of CALGB trial 9344 suggested paclitaxel administration following cyclophosphamide and doxorubicin adjuvant chemotherapy is most beneficial for patients with ERalpha negative (ERalpha-) breast cancer. Since the cytotoxic effects of paclitaxel are cell cycle dependent, we postulated that the relationship between ERalpha and the effectiveness of adjuvant paclitaxel reflects the observation that ERalpha positive (ERalpha+) breast cancers proliferate more slowly than ERalpha- breast cancers. Three in vitro models (MCF-7, T47D and ZR-75) were examined to compare growth rates and paclitaxel-induced apoptosis in ERalpha+ and ERalpha- clones of the same, originally ERalpha+ cell line. For the T47D and ZR-75 cell lines, loss of ERalpha was associated with a decrease in doubling time and an increase in paclitaxel sensitivity. However, when cell culture conditions were altered to achieve equivalent cell proliferation rates, no difference in paclitaxel sensitivity was observed. Similarly, an ERalpha- clone of MCF-7 cells that did not exhibit an enhanced growth rate compared to its ERalpha+ counterpart also did not show increased paclitaxel sensitivity. The combined apoptotic effects of tamoxifen and paclitaxel on MCF-7 cells were not synergistic or even clearly additive. In these in vitro models, the effectiveness of paclitaxel correlated more closely with growth rate than ERalpha expression. These data suggest that measurements of tumor proliferation may provide more accurate predictive markers for the benefits of adjuvant paclitaxel than ERalpha analysis.

Antineoplastic Agents, Phytogenic↗

PubMed2004

Unlocking the code of 14-3-3.

One of the most striking 'rags to riches' stories in the protein world is that of 14-3-3, originally identified in 1967 as merely an abundant brain protein. The first clues that 14-3-3 would play an important role in cell biology came almost 25 years later when it was found to interact with various proto-oncogene proteins and signaling proteins. The subsequent identification of 14-3-3 as a phosphoserine/phosphothreonine-binding protein firmly established its importance in cell signaling. 14-3-3 family members are found in all eukaryotes - from plants to mammals - and more than 100 binding partners have been identified to date. The targets of 14-3-3 are found in all subcellular compartments and their functional diversity is overwhelming - they include transcription factors, biosynthetic enzymes, cytoskeletal proteins, signaling molecules, apoptosis factors and tumor suppressors. 14-3-3 binding can alter the localization, stability, phosphorylation state, activity and/or molecular interactions of a target protein. Recent studies now indicate that the serine/threonine protein phosphatases PP1 and PP2A are important regulators of 14-3-3 binding interactions, and demonstrate a role for 14-3-3 in controlling the translocation of certain proteins from the cytoplasmic and endoplasmic reticulum to the plasma membrane. New reports also link 14-3-3 to several neoplastic and neurological disorders, where it might contribute to the pathogenesis and progression of these diseases.

14-3-3 Proteins↗