April Weissmiller

Dr. April Weissmiller

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Academic Career Length

15Years (2012-Present)

(Calculated once Scilit publication data is synced: current year − year of first publication + 1)

Representative Publications

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11 April 2016 in Journal of Clinical Investigation
Verified
Journal Article
Open access
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WXWei Xu
Wei Xu
AWApril Weissmiller
April Weissmiller
JWJoseph A. White
Joseph A. White
FFFang Fang
Fang Fang
XWXinyi Wang
Xinyi Wang
Chengbiao WuChengbiao Wu
Chengbiao Wu
The endosome/lysosome pathway is disrupted early in the course of both Alzheimer’s disease (AD) and Down syndrome (DS); however, it is not clear how dysfunction in this pathway influences the development of these diseases. Herein, we explored the cellular and molecular mechanisms by which endosomal dysfunction contributes to the pathogenesis of AD and DS. We determined that full-length amyloid precursor protein (APP) and its β-C-terminal fragment (β-CTF) act though increased activation of Rab5 to cause enlargement of early endosomes and to disrupt retrograde axonal trafficking of nerve growth factor (NGF) signals. The functional impacts of APP and its various products were investigated in PC12 cells, cultured rat basal forebrain cholinergic neurons (BFCNs), and BFCNs from a mouse model of DS. We found that the full-length wild-type APP (APPWT) and β-CTF both induced endosomal enlargement and disrupted NGF signaling and axonal trafficking. β-CTF alone induced atrophy of BFCNs that was rescued by the dominant-negative Rab5 mutant, Rab5S34N. Moreover, expression of a dominant-negative Rab5 construct markedly reduced APP-induced axonal blockage in Drosophila. Therefore, increased APP and/or β-CTF impact the endocytic pathway to disrupt NGF trafficking and signaling, resulting in trophic deficits in BFCNs. Our data strongly support the emerging concept that dysregulation of Rab5 activity contributes importantly to early pathogenesis of AD and DS.
26 July 2012 in Translational Neurodegeneration
Verified
Journal Article
Open access
AWApril Weissmiller
April Weissmiller
Chengbiao WuChengbiao Wu
Chengbiao Wu
Neurotrophic factors are best known for their roles in both development and continued maintenance of the nervous system. Their strong potential to elicit pro-survival and pro-functional responses in neurons of the peripheral and central nervous system make them good drug candidates for treatment of a multitude of neurodegenerative disorders. However, significant obstacles remain and need to be overcome before translating the potential of neurotrophins into the therapeutic arena. This article addresses current efforts and advances in resolving these challenges and provides an overview of roadmaps for future translational research and neurotrophin-based drug developments.
1 March 2019 in Cell Reports
Verified
Journal Article
Open access
EAErin R. Aho
Erin R. Aho
JWJing Wang
Jing Wang
RGRocco D. Gogliotti
Rocco D. Gogliotti
GHGregory C. Howard
Gregory C. Howard
JPJason Phan
Jason Phan
WTWilliam Tansey
William Tansey
The chromatin-associated protein WDR5 is a promising target for pharmacological inhibition in cancer. Drug discovery efforts center on the blockade of the "WIN site" of WDR5, a well-defined pocket that is amenable to small molecule inhibition. Various cancer contexts have been proposed to be targets for WIN site inhibitors, but a lack of understanding of WDR5 target genes and of the primary effects of WIN site inhibitors hampers their utility. Here, by the discovery of potent WIN site inhibitors, we demonstrate that the WIN site links WDR5 to chromatin at a small cohort of loci, including a specific subset of ribosome protein genes. WIN site inhibitors rapidly displace WDR5 from chromatin and decrease the expression of associated genes, causing translational inhibition, nucleolar stress, and p53 induction. Our studies define a mode by which WDR5 engages chromatin and forecast that WIN site blockade could have utility against multiple cancer types.
1 May 2019 in Nature Communications
Verified
Journal Article
Open access
PDF file
AWApril Weissmiller
April Weissmiller
JWJing Wang
Jing Wang
SLShelly L. Lorey
Shelly L. Lorey
GHGregory C. Howard
Gregory C. Howard
EMErnest Martinez
Ernest Martinez
WTWilliam Tansey
William Tansey
SMARCB1 encodes the SNF5 subunit of the SWI/SNF chromatin remodeler. SNF5 also interacts with the oncoprotein transcription factor MYC and is proposed to stimulate MYC activity. The concept that SNF5 is a coactivator for MYC, however, is at odds with its role as a tumor-suppressor, and with observations that loss of SNF5 leads to activation of MYC target genes. Here, we reexamine the relationship between MYC and SNF5 using biochemical and genome-wide approaches. We show that SNF5 inhibits the DNA-binding ability of MYC and impedes target gene recognition by MYC in cells. We further show that MYC regulation by SNF5 is separable from its role in chromatin remodeling, and that reintroduction of SNF5 into SMARCB1-null cells mimics the primary transcriptional effects of MYC inhibition. These observations reveal that SNF5 antagonizes MYC and provide a mechanism to explain how loss of SNF5 can drive malignancy.
1 January 2021 in Cell Reports
Verified
Journal Article
Open access
AGAlissa D. Guarnaccia
Alissa D. Guarnaccia
KRKristie L. Rose
Kristie L. Rose
JWJing Wang
Jing Wang
BZBin Zhao
Bin Zhao
TPTessa M. Popay
Tessa M. Popay
WTWilliam Tansey
William Tansey
The chromatin-associated protein WDR5 is a promising pharmacological target in cancer, with most drug discovery efforts directed against an arginine-binding cavity in WDR5 called the WIN site. Despite a clear expectation that WIN site inhibitors will alter the repertoire of WDR5 interaction partners, their impact on the WDR5 interactome remains unknown. Here, we use quantitative proteomics to delineate how the WDR5 interactome is changed by WIN site inhibition. We show that the WIN site inhibitor alters the interaction of WDR5 with dozens of proteins, including those linked to phosphatidylinositol 3-kinase (PI3K) signaling. As proof of concept, we demonstrate that the master kinase PDPK1 is a bona fide high-affinity WIN site binding protein that engages WDR5 to modulate transcription of genes expressed in the G2 phase of the cell cycle. This dataset expands our understanding of WDR5 and serves as a resource for deciphering the action of WIN site inhibitors.
30 September 2015 in Cancer Research
Verified
Journal Article
Closed access
PDF file
LTLance R. Thomas
Lance R. Thomas
AFAudra M. Foshage
Audra M. Foshage
AWApril Weissmiller
April Weissmiller
WTWilliam Tansey
William Tansey
The MYC oncogenes encode a family of transcription factors that feature prominently in cancer. MYC proteins are overexpressed or deregulated in a majority of malignancies and drive tumorigenesis by inducing widespread transcriptional reprogramming that promotes cell proliferation, metabolism, and genomic instability. The ability of MYC to regulate transcription depends on its dimerization with MAX, which creates a DNA-binding domain that recognizes specific sequences in the regulatory elements of MYC target genes. Recently, we discovered that recognition of target genes by MYC also depends on its interaction with WDR5, a WD40-repeat protein that exists as part of several chromatin-regulatory complexes. Here, we discuss how interaction of MYC with WDR5 could create an avidity-based chromatin recognition mechanism that allows MYC to select its target genes in response to both genetic and epigenetic determinants. We rationalize how the MYC–WDR5 interaction provides plasticity in target gene selection by MYC and speculate on the biochemical and genomic contexts in which this interaction occurs. Finally, we discuss how properties of the MYC–WDR5 interface make it an attractive point for discovery of small-molecule inhibitors of MYC function in cancer cells. Cancer Res; 75(19); 4012–5. ©2015 AACR.