Obstetricians & Gynecologists
15 years of experience

Northwest Dallas
4606 Cedar Springs Rd
Apt 1736
Dallas, TX 75219
Locations and availability (2)

Education ?

Medical School Score
Saint Louis University (1995)
  • Currently 2 of 4 apples

Awards & Distinctions ?

Associations
American Board of Obstetrics and Gynecology

Publications & Research

Dr. Mahoney has contributed to 13 publications.
Title Mob4 Plays a Role in Spindle Focusing in Drosophila S2 Cells.
Date August 2008
Journal Journal of Cell Science
Excerpt

The characteristic bipolar shape of the mitotic spindle is produced by the focusing of the minus ends of microtubules at the spindle poles. The focus is maintained by the centrosome, a microtubule-nucleating organelle, as well as by proteins that are capable of focusing kinetochore fibers (K fibers) even in the absence of a centrosome. Here, we have performed a small-scale RNA interference (RNAi) screen of known or suspected pole-related proteins in Drosophila S2 cells. An unexpected outcome of this screen was the finding that one of the four Drosophila Mob proteins (a family of kinase regulators) plays a role in spindle pole organization. Time-lapse microscopy of mitotic cells depleted of Drosophila Mob4 by RNAi revealed that the K fibers splay apart and do not maintain their focus either in the presence or absence of functional centrosomes. The Mob4 RNAi phenotype most closely resembles that observed after depletion of the protein encoded by abnormal spindle (Asp), although Asp localization is not substantially affected by Mob4 RNAi. Expression of a Drosophila Mob4-GFP fusion protein revealed its localization to the nucleus in interphase and to spindle poles and kinetochores during mitosis. We propose that Mob4 in Drosophila controls a mitotic kinase that in turn regulates downstream target proteins involved in K fiber focusing at the poles.

Title Making Microtubules and Mitotic Spindles in Cells Without Functional Centrosomes.
Date July 2006
Journal Current Biology : Cb
Excerpt

Centrosomes are considered to be the major sites of microtubule nucleation in mitotic cells (reviewed in ), yet mitotic spindles can still form after laser ablation or disruption of centrosome function . Although kinetochores have been shown to nucleate microtubules, mechanisms for acentrosomal spindle formation remain unclear. Here, we performed live-cell microscopy of GFP-tubulin to examine spindle formation in Drosophila S2 cells after RNAi depletion of either gamma-tubulin, a microtubule nucleating protein, or centrosomin, a protein that recruits gamma-tubulin to the centrosome. In these RNAi-treated cells, we show that poorly focused bipolar spindles form through the self-organization of microtubules nucleated from chromosomes (a process involving gamma-tubulin), as well as from other potential sites, and through the incorporation of microtubules from the preceding interphase network. By tracking EB1-GFP (a microtubule-plus-end binding protein) in acentrosomal spindles, we also demonstrate that the spindle itself represents a source of new microtubule formation, as suggested by observations of numerous microtubule plus ends growing from acentrosomal poles toward the metaphase plate. We propose that the bipolar spindle propagates its own architecture by stimulating microtubule growth, thereby augmenting the well-described microtubule nucleation pathways that take place at centrosomes and chromosomes.

Title Phased Translation Function Revisited: Structure Solution of the Cofilin-homology Domain from Yeast Actin-binding Protein 1 Using Six-dimensional Searches.
Date August 2005
Journal Acta Crystallographica. Section D, Biological Crystallography
Excerpt

A modified molecular-replacement method is described that makes use of six-dimensional searches and the phased translation function, providing a systematic examination of all possible search-model orientations in an experimental electron-density map. As an example, the structure solution of the cofilin-homology domain of the Saccharomyces cerevisiae actin-binding protein 1 (ABP1) is presented in detail. Additional examples are presented in which these tools have significantly aided structure solutions in a variety of contexts. These results suggest that this approach might be of widespread utility for challenging structures involving weak phase information, complex asymmetric units and search models with weak structural homology. Furthermore, this approach supports an exhaustive molecular-replacement strategy in cases where an appropriate search model cannot readily be identified on the basis of sequence homology. The fully automated web-based implementation of this phased translation function is described.

Title Laparoscopic Management of Urolithiasis in a Continent Urostomy.
Date March 2002
Journal Gynecologic Oncology
Excerpt

BACKGROUND: Urinary calculi formation is an infrequent but challenging late complication of continent urostomy. Percutaneous endoscopic management of two patients with symptomatic pouch urolithiasis is described. CASES: A 48-year-old woman with a history of cervical squamous cell carcinoma (SCC) treated with primary chemoradiotherapy presented with recurrent pain and urinary tract infections (pouchitis). She had undergone continent urostomy 4 years previously for management of a vesicovaginal fistula. A 59-year-old woman following exenteration with continent diversion for recurrent cervix SCC had a 6-month history of refractory pouchitis. In both women, multiple pouch urinary calculi were identified. Their continent reservoirs were, in part, created using titanium staplers. Percutaneous CO(2) endoscopy afforded identification and removal of their stones and staples without complication. CONCLUSION: Successful treatment of continent urostomy urolithiasis is accomplished by percutaneous endoscopy.

Title Germline Brca1-2 Mutations in Non-ashkenazi Families with Double Primary Breast and Ovarian Cancer.
Date December 2001
Journal Gynecologic Oncology
Excerpt

OBJECTIVE: Ashkenazi women with double primary breast and ovarian cancer have a high prevalence (57%) of germline Jewish founder mutations in the BRCA1 (185delAG, 5382insC) and BRCA2 (6174delT) genes. The purpose of this study was to determine the frequency and type of BRCA1-2 mutations in non-Ashkenazi families with at least one member having double primary breast and ovarian cancer. METHODS: Women at increased risk for cancer based upon their family history were enrolled at the University of Texas Southwestern Familial Cancer Registry between 1992 and 2000. Blood samples from patients desiring genetic testing were sent for complete DNA sequencing of the BRCA1 and BRCA2 genes. Families with a member having both breast and ovarian cancer were identified and clinical data were obtained. RESULTS: Sixty-two (7%) of 900 enrolled families were non-Ashkenazi and had at least one member with double primary breast and ovarian cancer. Twenty-one families had members who underwent genetic testing; 41 did not. Thirteen (62%) families had a germline BRCA1 (n = 11) or BRCA2 (n = 2) mutation; only one Jewish founder mutation (185delAG) was detected. Eight (38%) families tested negative. Six (86%) of seven women undergoing genetic testing who themselves had double primary breast and ovarian cancer were BRCA1-2 mutation carriers. CONCLUSIONS: Germline BRCA1-2 mutations are common in non-Ashkenazi families with a member having double primary breast and ovarian cancer. These mutations occurred throughout both genes, emphasizing the need for comprehensive sequencing. One family had the BRCA2 6985delCT mutation, which lies beyond the "ovarian cancer cluster" region.

Title In Vivo Importance of Actin Nucleotide Exchange Catalyzed by Profilin.
Date September 2000
Journal The Journal of Cell Biology
Excerpt

The actin monomer-binding protein, profilin, influences the dynamics of actin filaments in vitro by suppressing nucleation, enhancing nucleotide exchange on actin, and promoting barbed-end assembly. Profilin may also link signaling pathways to actin cytoskeleton organization by binding to the phosphoinositide PIP(2) and to polyproline stretches on several proteins. Although activities of profilin have been studied extensively in vitro, the significance of each of these activities in vivo needs to be tested. To study profilin function, we extensively mutagenized the Saccharomyces cerevisiae profilin gene (PFY1) and examined the consequences of specific point mutations on growth and actin organization. The actin-binding region of profilin was shown to be critical in vivo. act1-157, an actin mutant with an increased intrinsic rate of nucleotide exchange, suppressed defects in actin organization, cell growth, and fluid-phase endocytosis of pfy1-4, a profilin mutant defective in actin binding. In reactions containing actin, profilin, and cofilin, profilin was required for fast rates of actin filament turnover. However, Act1-157p circumvented the requirement for profilin. Based on the results of these studies, we conclude that in living cells profilin promotes rapid actin dynamics by regenerating ATP actin from ADP actin-cofilin generated during filament disassembly.

Title Profilin is Required for Optimal Actin-dependent Transcription of Respiratory Syncytial Virus Genome Rna.
Date February 2000
Journal Journal of Virology
Excerpt

Transcription of human respiratory syncytial virus (RSV) genome RNA exhibited an obligatory need for the host cytoskeletal protein actin. Optimal transcription, however, required the participation of another cellular protein that was characterized as profilin by a number of criteria. The amino acid sequence of the protein, purified on the basis of its transcription-optimizing activity in vitro, exactly matched that of profilin. RSV transcription was inhibited 60 to 80% by antiprofilin antibody or poly-L-proline, molecules that specifically bind profilin. Native profilin, purified from extracts of lung epithelial cells by affinity binding to a poly-L-proline matrix, stimulated the actin-saturated RSV transcription by 2.5- to 3-fold. Recombinant profilin, expressed in bacteria, stimulated viral transcription as effectively as the native protein and was also inhibited by poly-L-proline. Profilin alone, in the absence of actin, did not activate viral transcription. It is estimated that at optimal levels of transcription, every molecule of viral genomic RNA associates with approximately the following number of protein molecules: 30 molecules of L, 120 molecules of phosphoprotein P, and 60 molecules each of actin and profilin. Together, these results demonstrated for the first time a cardinal role for profilin, an actin-modulatory protein, in the transcription of a paramyxovirus RNA genome.

Title Profilin Binds Proline-rich Ligands in Two Distinct Amide Backbone Orientations.
Date August 1999
Journal Nature Structural Biology
Excerpt

The actin regulatory protein profilin is targeted to specific cellular regions through interactions with highly proline-rich motifs embedded within its binding partners. New X-ray crystallographic results demonstrate that profilin, like SH3 domains, can bind proline-rich ligands in two distinct amide backbone orientations. By further analogy with SH3 domains, these data suggest that non-proline residues in profilin ligands may dictate the polarity and register of binding, and the detailed organization of the assemblies involving profilin. This degeneracy may be a general feature of modules that bind proline-rich ligands, including WW and EVH1 domains, and has implications for the assembly and activity of macromolecular complexes involved in signaling and the regulation of the actin cytoskeleton.

Title Crystallization and Preliminary X-ray Analysis of Human Platelet Profilin Complexed with an Oligo Proline Peptide.
Date November 1998
Journal Acta Crystallographica. Section D, Biological Crystallography
Excerpt

Profilin is an actin-monomer binding protein that regulates the distribution and dynamics of the actin cytoskeleton. Profilin binds poly-L-proline and proline-rich peptides in vitro and co-localizes with proline-rich proteins in focal adhesions and at the site of actin tail assembly on the surface of intracellular parasites such as Listeria monocytogenes. The crystallization of the complex between human platelet profilin (HPP) and an L-proline decamer [(Pro)10] is reported here. Diffraction from these crystals is consistent with the space group P21212 with unit-cell constants a = 68.25, b = 97.64, c = 39.10 A. The crystals contain two HPP molecules per asymmetric unit and diffract to 2.2 A.

Title Structure Determination and Characterization of Saccharomyces Cerevisiae Profilin.
Date September 1998
Journal Biochemistry
Excerpt

The structure of profilin from the budding yeast Saccharomyces cerevisiae has been determined by X-ray crystallography at 2.3 A resolution. The overall fold of yeast profilin is similar to the fold observed for other profilin structures. The interactions of yeast and human platelet profilins with rabbit skeletal muscle actin were characterized by titration microcalorimetry, fluorescence titrations, and nucleotide exchange kinetics. The affinity of yeast profilin for rabbit actin (2.9 microM) is approximately 30-fold weaker than the affinity of human platelet profilin for rabbit actin (0.1 microM), and the relative contributions of entropic and enthalpic terms to the overall free energy of binding are different for the two profilins. The titration of pyrene-labeled rabbit skeletal actin with human profilin yielded a Kd of 2.8 microM, similar to the Kd of 2.0 microM for the interaction between yeast profilin and pyrene-labeled yeast actin. The binding data are discussed in the context of the known crystal structures of profilin and actin, and the residues present at the actin-profilin interface. The affinity of yeast profilin for poly-L-proline was determined from fluorescence measurements and is similar to the reported affinity of Acanthamoeba profilin for poly-L-proline. Yeast profilin was shown to catalyze adenine nucleotide exchange from yeast actin almost 2 orders of magnitude less efficiently than human profilin and rabbit skeletal muscle actin. The in vivo and in vitro properties of yeast profilin mutants with altered poly-L-proline and actin binding sites are discussed in the context of the crystal structure.

Title The Modular Structure of Actin-regulatory Proteins.
Date April 1998
Journal Current Opinion in Cell Biology
Excerpt

Filamentous actin structures possess unique biophysical and biochemical properties and are required for cell locomotion, cell division, compartmentalization and morphological processes. The site-specific assembly and disassembly of these structures are directed by actin-regulatory proteins. This article reviews how structural studies are now defining the atomic details of small modular domains present in actin-regulatory proteins responsible for crosslinking, severing and capping of actin filaments, as well as for localization of actin filament assembly. These studies have identified three modular strategies for the design of proteins that regulate the actin cytoskeleton.

Title Structure of the Profilin-poly-l-proline Complex Involved in Morphogenesis and Cytoskeletal Regulation.
Date December 1997
Journal Nature Structural Biology
Excerpt

Profilin, a ubiquitous low molecular weight (13,000-15,000 M(r)) actin binding protein, regulates the formation of F-actin structures in vivo, and is localized to specific cellular regions through interaction with proline-rich sequences. Here we report the 2.2 A X-ray structure of the complex between human platelet profilin (HPP) and a decamer of L-proline (L-Pro10). The L-Pro10 peptide adopts a left-handed type II poly-L-proline helix (PPII) and binds to a highly conserved patch of aromatic amino acids on the surface of profilin. The peptide and actin binding sites reside on orthogonal surfaces, and L-Pro10 binding does not result in a conformational rearrangement of HPP. This structure suggests a mechanism for the localization of profilin and its actin-related activities to sites of actin filament assembly in vivo.

Title The Molecular Basis for Allergen Cross-reactivity: Crystal Structure and Ige-epitope Mapping of Birch Pollen Profilin.
Date February 1997
Journal Structure (london, England : 1993)
Excerpt

The profilins are a group of ubiquitous actin monomer binding proteins that are responsible for regulating the normal distribution of filamentous actin networks in eukaryotic cells. Profilins also bind polyphosphoinositides, which can disrupt the profilin-action complex, and proline-rich ligands which localize profilin to sites requiring extensive actin filament accumulation. Profilins represent cross-reactive allergens for almost 20 % of all pollen allergic patients.


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