Tony Boutelle teaches in the Civic, Liberal, and Global Education (COLLEGE) program. He earned a B.S. in Biology with a second major in Chemistry at the University of North Carolina at Chapel Hill. During his time at Chapel Hill, he conducted undergraduate research in the Alisa Wolberg Lab, studying the biochemistry of blood clotting and completing an honors thesis entitled "Investigating the binding interaction between human factor XIII and fibrinogen". Motivated to continue conducting research to understand biological processes that impact human health, he went on to complete a Ph.D. in Cancer Biology at the Stanford School of Medicine, studying cancer genetics and cell biology in the Laura Attardi Lab. His dissertation, entitled "Understanding tumor suppression through the p53 target gene network", focused on illuminating the downstream effectors of the potent tumor suppressor, p53, and the molecular and cellular mechanisms important for tumor suppression.
Tony discovered his love for teaching as a supplemental instructor for "Principles of Biology" during his Junior and Senior years at UNC. At Stanford he served as a graduate teaching assistant for "Molecular and Genetic Basis of Cancer" and "Cancer Biology" and took on mentoring and outreach roles with various programs including REACH, GRIPS, PIPS, the Ashanti Project, EXPLORE, SIMR, Hermanxs in STEM, and Stanford SPLASH. Tony enjoys exploring the intersection of the "hard" sciences with other disciplines such as religion, philosophy, literature, etc. Through teaching, Tony hopes to create spaces that encourage students and instructors alike to gain the skills and confidence to create a meaningful life for themselves and to shape communities that promote human flourishing.
In his free time, find Tony bird watching, baking, playing a board game, or trying a new food.
Lecturer, Stanford Introductory Studies - Civic, Liberal, and Global Education
The Mettl3 epitranscriptomic writer amplifies p53 stress responses.
The p53 transcription factor drives anti-proliferative gene expression programs in response to diverse stressors, including DNA damage and oncogenic signaling. Here, we seek to uncover new mechanisms through which p53 regulates gene expression using tandem affinity purification/mass spectrometry to identify p53-interacting proteins. This approach identified METTL3, an m6A RNA-methyltransferase complex (MTC) constituent, as a p53 interactor. We find that METTL3 promotes p53 protein stabilization and target gene expression in response to DNA damage and oncogenic signals, by both catalytic activity-dependent and independent mechanisms. METTL3 also enhances p53 tumor suppressor activity in invivo mouse cancer models and human cancer cells. Notably, METTL3 only promotes tumor suppression in the context of intact p53. Analysis of human cancer genome data further supports the notion that the MTC reinforces p53 function in human cancer. Together, these studies reveal a fundamental role for METTL3 in amplifying p53 signaling in response to cellular stress.
View details for DOI 10.1016/j.molcel.2022.04.010
View details for PubMedID 35512709
p53 and Tumor Suppression: It Takes a Network.
Trends in cell biology
The TP53 tumor suppressor is the most frequently mutated gene in human cancer. p53 suppresses tumorigenesis by transcriptionally regulating a network of target genes that play roles in various cellular processes. Though originally characterized as a critical regulator for responses to acute DNA damage (activation of apoptosis and cell cycle arrest), recent studies have highlighted new pathways and transcriptional targets downstream of p53 regulating genomic integrity, metabolism, redox biology, stemness, and non-cell autonomous signaling in tumor suppression. Here, we summarize our current understanding of p53-mediated tumor suppression, situating recent findings from mouse models and unbiased screens in the context of previous studies and arguing for the importance of the pleiotropic effects of the p53 transcriptional network in inhibiting cancer.
View details for DOI 10.1016/j.tcb.2020.12.011
View details for PubMedID 33518400
Zmat3 Is a Key Splicing Regulator in the p53 Tumor Suppression Program.
2020; 80 (3): 452
Although TP53 is the most commonly mutated gene in human cancers, the p53-dependent transcriptional programs mediating tumor suppression remain incompletely understood. Here, to uncover critical components downstream of p53 in tumor suppression, we perform unbiased RNAi and CRISPR-Cas9-based genetic screens invivo. These screens converge upon the p53-inducible gene Zmat3, encoding an RNA-binding protein, and we demonstrate that ZMAT3 is an important tumor suppressor downstream of p53 in mouse KrasG12D-driven lung and liver cancers and human carcinomas. Integrative analysis of the ZMAT3 RNA-binding landscape and transcriptomic profiling reveals that ZMAT3 directly modulates exon inclusion in transcripts encoding proteins of diverse functions, including the p53 inhibitors MDM4 and MDM2, splicing regulators, and components of varied cellular processes. Interestingly, these exons are enriched in NMD signals, and, accordingly, ZMAT3 broadly affects target transcript stability. Collectively, these studies reveal ZMAT3 as a novel RNA-splicing and homeostasis regulator and a key component of p53-mediated tumor suppression.
View details for DOI 10.1016/j.molcel.2020.10.022
View details for PubMedID 33157015
p53 deficiency triggers dysregulation of diverse cellular processes in physiological oxygen.
The Journal of cell biology
2020; 219 (11)
The mechanisms by which TP53, the most frequently mutated gene in human cancer, suppresses tumorigenesis remain unclear. p53 modulates various cellular processes, such as apoptosis and proliferation, which has led to distinct cellular mechanisms being proposed for p53-mediated tumor suppression in different contexts. Here, we asked whether during tumor suppression p53 might instead regulate a wide range of cellular processes. Analysis of mouse and human oncogene-expressing wild-type and p53-deficient cells in physiological oxygen conditions revealed that p53 loss concurrently impacts numerous distinct cellular processes, including apoptosis, genome stabilization, DNA repair, metabolism, migration, and invasion. Notably, some phenotypes were uncovered only in physiological oxygen. Transcriptomic analysis in this setting highlighted underappreciated functions modulated by p53, including actin dynamics. Collectively, these results suggest that p53 simultaneously governs diverse cellular processes during transformation suppression, an aspect of p53 function that would provide a clear rationale for its frequent inactivation in human cancer.
View details for DOI 10.1083/jcb.201908212
View details for PubMedID 32886745
The interaction between fibrinogen and zymogen FXIII-A2B2 is mediated by fibrinogen residues γ390-396 and the FXIII-B subunits.
2016; 128 (15): 1969-1978
Coagulation transglutaminase factor XIII (FXIII) exists in circulation as heterotetrameric proenzyme FXIII-A2B2 Effectively all FXIII-A2B2 circulates bound to fibrinogen, and excess FXIII-B2 circulates in plasma. The motifs that mediate interaction of FXIII-A2B2 with fibrinogen have been elusive. We recently detected reduced binding of FXIII-A2B2 to murine fibrinogen that has γ-chain residues 390-396 mutated to alanines (Fibγ390-396A). Here, we evaluated binding features using human components, including recombinant fibrinogen variants, FXIII-A2B2, and isolated FXIII-A2 and -B2 homodimers. FXIII-A2B2 coprecipitated with wild-type (γA/γA), alternatively-spliced (γ'/γ'), and αC-truncated (Aα251) fibrinogens, whereas coprecipitation with human Fibγ390-396A was reduced by 75% (P <0001). Surface plasmon resonance showed γA/γA, γ'/γ', and Aα251 fibrinogens bound FXIII-A2B2 with high affinity (nanomolar); however, Fibγ390-396A did not bind FXIII-A2B2 These data indicate fibrinogen residues γ390-396 comprise the major binding motif for FXIII-A2B2 Compared with γA/γA clots, FXIII-A2B2 activation peptide release was 2.7-fold slower in Fibγ390-396A clots (P < .02). Conversely, activation of recombinant FXIII-A2 (lacking FXIII-B2) was similar in γA/γA and Fibγ390-396A clots, suggesting fibrinogen residues γ390-396 accelerate FXIII-A2B2 activation in a FXIII-B2-dependent mechanism. Recombinant FXIII-B2 bound γA/γA, γ'/γ', and Aα251 with similar affinities as FXIII-A2B2, but did not bind or coprecipitate with Fibγ390-396A FXIII-B2 also coprecipitated with fibrinogen from FXIII-A-deficient mouse and human plasmas. Collectively, these data indicate that FXIII-A2B2 binds fibrinogen residues γ390-396 via the B subunits, and that excess plasma FXIII-B2 is not free, but rather circulates bound to fibrinogen. These findings provide insight into assembly of the fibrinogen/FXIII-A2B2 complex in both physiologic and therapeutic situations.
View details for DOI 10.1182/blood-2016-04-712323
View details for PubMedID 27561317
View details for PubMedCentralID PMC5064719