Stathmin is a microtubule-destabilizing protein ubiquitously expressed in vertebrates and highly expressed in many cancers. In several cell types, stathmin regulates the partitioning of tubulin between unassembled and polymer forms, but the mechanism responsible for partitioning has not been determined. We examined stathmin function in two cell systems: mouse embryonic fibroblasts (

A fluorescently-labeled, persulfated molecular umbrella (1) has been synthesized from cholic acid, lysine, spermine and Coumarin 343 and found capable of entering live HeLa cells. The distribution of 1 throughout the cytoplasm and the nucleus was diffuse and punctate, respectively. This finding, together with its ability to cross liposomal membranes by passive diffusion, suggests that passive diffusion plays a significant role in the ability of 1 to enter cells. The fact that 1 is concentrated at the nucleus raises the possibility that molecular umbrellas of this type could be used for the nuclear targeting of drugs.Molecular umbrellas are a unique class of conjugates that are composed of two or more facial amphiphiles that are covalently bound to a central scaffold. Such molecules have been found to possess the ability of crossing liposomal membranes by passive diffusion. 1-4 Our working hypothesis has been that the amphiphilic "wings" of a molecular umbrella first bind to the surface of the liposomal membrane, that translocation proceeds through a shielded conformation in which the hydrophilic faces of the molecule point toward one another as it passes through the hydrocarbon interior, and that the umbrella is then released from the adjacent monolayer into the adjoining aqueous phase. In Scheme 1 we illustrate our current model for umbrella transport of a hydrophilic agent across a lipid bilayer. Here, the shaded and unshaded rectangles represent hydrophobic and hydrophilic faces of the facially amphiphilic units, respectively, and the lightly shaded oval represents a covalently attached, hydrophilic agent. Thus, the umbrella first approaches the membrane in a fully exposed conformation (structure A). Hydrophobic interactions with the membrane interior then leads to an adsorbed state in which the hydrophilic faces are in contact with the polar head group region and the hydrophobic faces are in intimate contact with the hydrocarbon region of the lipid bilayer (structure B). Subsquent absorption into the interior of the membrane, being driven by hydrophobic forces, then affords structure C. Translocation to the adjoining leaflet, 180° rotation and reversal of steps B and A (not shown) then releases the conjugate from the other side of the membrane. In essence, we have postulated that the molecular umbrella masks its own hydrophilicity as well as that of an attached polar agent as it crosses the hydrocarbon interior of the bilayer.In the work that is reported herein, we sought to answer a long-standing question that bears directly on the potential of molecular umbrellas as drug carriers. Specifically, can a molecular

Background: Stathmin (STMN1) protein functions to regulate assembly of the microtubule cytoskeleton by destabilizing microtubule polymers. Stathmin over-expression has been correlated with cancer stage progression, while stathmin depletion leads to death of some cancer cell lines in culture. In contrast, stathmin-null mice are viable with minor axonopathies and loss of innate fear response. Several stathmin binding partners, in addition to tubulin, have been shown to affect cell motility in culture. To expand our understanding of stathmin function in normal cells, we compared gene expression profiles, measured by microarray and qRT-PCR, of mouse embryo fibroblasts isolated from STMN1 +/+ and STMN1 -/-mice to determine the transcriptome level changes present in the genetic knock-out of stathmin.

Mutations in BRCA1 account for a significant proportion of hereditary breast and ovarian cancers, but analysis of BRCA1 function is complicated by pleiotropic effects and binding partners (Pol II holoenzyme and transcription factors, chromatin remodelers, recombination complexes and E3 ligases). In vertebrate cells, efforts to elucidate BRCA1 transcriptional effects have focused on specific genes or restricted portions of the genome—limiting analyses of BRCA1 effects on adjoining DNA sequences and along chromosome lengths. Here, we use microarray analyses on the genetically tractable yeast cell system to elucidate BRCA1-dependent genome-wide positional effects on both gene induction and repression. Yeast responses may be of clinical relevance based on findings that BRCA1 severely diminishes yeast growth kinetics but that BRCA1 mutated at sites identified from breast tumors is no longer able to retard yeast cell growth kinetics. Our analysis suggests that BRCA1 acts through both transcription factors to upregulate specific loci and chromatin remodeling complexes to effect global changes in gene expression. BRCA1 also exhibits gene repression activities. Cluster-functional analysis reveals that these repressed factors are required for mitotic stability and provide a novel molecular explanation for the conditional lethality observed between BRCA1 and chromosome segregation genes.

Faculty in STEM and administrators at the NCC-Monroe Campus recognized the importance of undergraduate research experiences as high-impact teaching practices but were realistic about the limitations of a two-year institution. As community and institutional partnerships are important in the creation of long-standing programs, faculty sought a community grant from a local pharmaceutical company, which provided the first NCC Stem Pipeline Project for 2016–2018.