Programmatic Foci of Women in Academic Leadership Positions at Historically Black Colleges and Universities: Intersectionality and Institutional Mission

The present studies compare, between Historically Black Colleges and Universities (HBCUs; n=102) and a non-HBCU cohort matched for location, religious and vocational mission, and student enrollment (comparator CUs; n=102), the programmatic foci of women in institutional leadership positions. They demonstrate that, at HBCUs, women are more prevalent in leadership roles with male-dominated foci (e.g., finance), and less prevalent in roles with female-dominated foci (e.g., public relations) than at comparator CUs (p \u3c 0.01). A survey of academic leaders (n=1,053 invited; 111 viewed survey; 83 completed survey) at these institutions indicates that women leaders at HBCUs more frequently fill institutional programmatic gaps than their counterparts at comparator CUs (p \u3c 0.001) or men in any academic setting (p \u3c 0.005). Reasons may include the social purpose of HBCUs; the stereotype threat of the traditional “service” role of women and the unique intersectionality encountered by Black women faculty; and the importance of race over gender in homosociability at HBCUs. This suggests that emphasis on the socioeconomic mission and philosophy of higher education may enhance faculty recruitment diversification efforts in higher education. It also raises the question of whether seeing women in atypical leadership roles influences the career aspirations and attitudes towards women leaders of the students, both men and women, at HBCUs

Role of tyrosine phosphorylation in the antioxidant effects of the p75 neurotrophin receptor

The p75 neurotrophin receptor (p75NTR) is an α-and γ-secretase substrate expressed preferentially in the cholinergic neurons of the nucleus basalis of Meynert, the hippocampus, and the cerebellum of the adult brain. Mutations of the γ-secretase, presenilin, have been implicated in familial Alzheimer's disease. Furthermore, oxidative and inflammatory injury to the cholinergic neurons of the nucleus basalis of Meynert and hippocampus plays a critical role in the pathology of Alzheimer's disease. The intracellular domain of p75NTR (p75ICD) is the α- and γ-secretase cleavage fragment of the holoreceptor that functions as an antioxidant in PC12 rat pheochromocytoma cells. Phosphorylation of the receptor is thought to be necessary for many of its functions, and two tyrosines in p75ICD have been among the functionally important phosphorylation sites. Site-directed mutagenesis was used to generate three p75ICD mutants that cannot be phosphorylated at either or both tyrosines, respectively. Each of these mutants was expressed in p75NTR-deficient PC12 cells to determine the effects of blocking phosphorylation at specific sites on the antioxidant activity of p75ICD. Interfering with phosphorylation at tyrosine-337 impairs antioxidant function, while interfering with phosphorylation at tyrosine-366 does not, and may in fact impart protection from oxidant stress. Neither MAPK (i.e., p38, ERK1, ERK2) content nor NF-κB activation accounts for the differential sensitivity to oxidant stress among the differentially phosphorylated p75NTR cell lines. However, differences in the time course of ERK1,2 phosphorylation among the lines account in large measure for their differential oxidant sensitivity. The phosphorylation state of specific sites on p75ICD may modulate the resistance of neurons in Alzheimer's disease-relevant brain regions to oxidant stress

Chopper Is Prodeath Regardless of the Effect of p75ICD on Sensitivity to Oxidative Stress

Background. The intracellular domain (ICD) of the neurotrophin receptor, p75NTR, exhibits variably pro- and antiapoptotic activity and has been implicated in neurodegenerative and neurodestructive disease. The molecular determinants of these cellular effects are not completely understood. The “Chopper” domain of p75ICD has been shown to be proapoptotic in in vitro systems in which p75ICD is proapoptotic. The effects of Chopper in systems in which p75ICD is antiapoptotic and, therefore, whether or not Chopper accounts for the variability of the cellular effects of p75ICD are not known. We therefore examined the effects of deletion of Chopper on the effects of p75ICD on in vitro cell culture systems in which p75ICD is pro- or antiapoptotic, respectively. Results. In HN33.11 murine neuroblastoma-hippocampal neuron hybrid cells, p75ICD is antiapoptotic. In NIH 3T3 cells, p75ICD is proapoptotic. In both cell lines deletion of the Chopper domain from p75ICD decreases the incidence of apoptosis resulting from oxidative stress. Thus, irrespective of the nature of the effects of p75ICD on the cell, its Chopper domain is proapoptotic. Conclusions. Expression of p75ICD can enhance or attenuate oxidative induction of apoptosis. Variability of the effects of p75ICD is not related to variability of the effects of its Chopper domain

PRMT1 promotes neuroblastoma cell survival through ATF5

Aberrant expression of protein arginine methyltransferases (PRMTs) has been implicated in a number of cancers, making PRMTs potential therapeutic targets. But it remains not well understood how PRMTs impact specific oncogenic pathways. We previously identified PRMTs as important regulators of cell growth in neuroblastoma, a deadly childhood tumor of the sympathetic nervous system. Here, we demonstrate a critical role for PRMT1 in neuroblastoma cell survival. PRMT1 depletion decreased the ability of murine neuroblastoma sphere cells to grow and form spheres, and suppressed proliferation and induced apoptosis of human neuroblastoma cells. Mechanistic studies reveal the prosurvival factor, activating transcription factor 5 (ATF5) as a downstream effector of PRMT1-mediated survival signaling. Furthermore, a diamidine class of PRMT1 inhibitors exhibited anti-neuroblastoma efficacy both in vitro and in vivo. Importantly, overexpression of ATF5 rescued cell apoptosis triggered by PRMT1 inhibition genetically or pharmacologically. Taken together, our findings shed new insights into PRMT1 signaling pathway, and provide evidence for PRMT1 as an actionable therapeutic target in neuroblastoma

Identification of a Vitamin-D Receptor Antagonist, MeTC7, which Inhibits the Growth of Xenograft and Transgenic Tumors In Vivo

Vitamin-D receptor (VDR) mRNA is overexpressed in neuroblastoma and carcinomas of lung, pancreas, and ovaries and predicts poor prognoses. VDR antagonists may be able to inhibit tumors that overexpress VDR. However, the current antagonists are arduous to synthesize and are only partial antagonists, limiting their use. Here, we show that the VDR antagonist MeTC7 (5), which can be synthesized from 7-dehydrocholesterol (6) in two steps, inhibits VDR selectively, suppresses the viability of cancer cell-lines, and reduces the growth of the spontaneous transgenic TH-MYCN neuroblastoma and xenografts in vivo. The VDR selectivity of 5 against RXRα and PPAR-γ was confirmed, and docking studies using VDR-LBD indicated that 5 induces major changes in the binding motifs, which potentially result in VDR antagonistic effects. These data highlight the therapeutic benefits of targeting VDR for the treatment of malignancies and demonstrate the creation of selective VDR antagonists that are easy to synthesize

Novel Approaches for Targeting Undifferentiated Cells in Neuroblastoma

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Neurobiology and Anatomy, 2013.Neuroblastoma is a pediatric tumor of the peripheral nervous system that manifests itself in two distinct forms. The first is a highly aggressive, and often fatal, tumor that grows uncontrollably, eventually metastasizing to distant organs. The second type grows initially, and even metastasizes in exceptional cases, but at a certain point regresses spontaneously and unexpectedly. One route for tumor regression is differentiation of the cancer cells to a benign collection of neural and Schwann cells called a ganglioma. Through histologic, proteomic, and genetic characterization clinicians can predict which tumors will regress; however, there are no effective treatments to induce differentiation in aggressive primary tumors or to specifically target the undifferentiated cells. In these studies, we report on our investigations to find treatments that work by these mechanisms. We have identified kinase D-interacting substrate of 220 kDa (Kidins220) as a potential target for neuroblastoma treatment. Kidins220 is a large multi-domain protein that interacts with both neurotrophic receptors and microtubule associated proteins among others. We have shown that Kidins220 is expressed in neuroblastoma tumors and cell lines. The results show that depletion of Kidins220 leads to attenuation of neurotrophic signaling, a factor in neuroblastoma cell survival. Kidins220 silencing also causes morphologic differentiation of neuroblastoma cells from neural-type cells that are associated with poor prognosis to stromal or Schwann-like cells that are indicative of differentiating tumors. These changes in morphology correlate with changes in expression of microtubule related genes including Dcx and Stmn2. Another strategy for eliminating undifferentiated cells is to use cytotoxic therapies that selectively target cells based on their protein expression. We show that the toxicity of the chemotherapeutic agent, neocarzinostatin (NCS), correlates with the Bcl-2 and caspase-3 expression in various human tumor cell lines. This combination of proteins is expressed highly in neuroblastoma cells as compared to other tumor types. Importantly for neuroblastoma therapy, the undifferentiated, neural-type, cells in neuroblastic tumors have higher expression of Bcl-2 which correlates with higher susceptibility to NCS. In consequence of these studies, both Kidins220 and NCS deserve further investigation as new ways to target undifferentiated cells in neuroblastoma

Cell Line-Dependent Variability of Coordinate Expression of p75NTR and CRABP1 and Modulation of Effects of Fenretinide on Neuroblastoma Cells

Neuroblastoma is a childhood neural crest tumor. Fenretinide, a retinoic acid analogue, induces accumulation of mitochondrial reactive oxygen species and consequent apoptosis in neuroblastoma cells. The p75 neurotrophin receptor (p75NTR) enhances the antineuroblastoma cell efficacy of fenretinide in vitro. We examined the role of the retinoid binding protein, CRABP1, in p75NTR-mediated potentiation of the efficacy of fenretinide. Knockdown and overexpression, respectively, of either p75NTR or CRABP1 were effected in neuroblastoma cell lines using standard techniques. Expression was determined by qRT-PCR and confirmed at the protein level by Western blot. Metabolic viability was determined by Alamar blue assay. While protein content of CRABP1 correlated roughly with that of p75NTR in the three neuroblastoid or epithelioid human neuroblastoma cell lines studied, manipulation of p75NTR expression resulted in cell line-dependent, variable change in CRABP1 expression. Furthermore, in some cell lines, induced expression of CRABP1 in the absence of p75NTR did not alter cell sensitivity to fenretinide treatment. The effects of manipulation of p75NTR expression on CRABP1 expression and the effects of CRABP1 expression on fenretinide efficacy are therefore neuroblastoma cell line-dependent. Potentiation of the antineuroblastoma cell effects of fenretinide by p75NTR is not mediated solely through CRABP1