Publications by authors named "Jacob McClendon"

6 Publications

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Trauma-induced regulation of VHP-1 modulates the cellular response to mechanical stress.

Nat Commun 2021 03 5;12(1):1484. Epub 2021 Mar 5.

Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA.

Mechanical stimuli initiate adaptive signal transduction pathways, yet exceeding the cellular capacity to withstand physical stress results in death. The molecular mechanisms underlying trauma-induced degeneration remain unclear. In the nematode C. elegans, we have developed a method to study cellular degeneration in response to mechanical stress caused by blunt force trauma. Herein, we report that physical injury activates the c-Jun kinase, KGB-1, which modulates response elements through the AP-1 transcriptional complex. Among these, we have identified a dual-specificity MAPK phosphatase, VHP-1, as a stress-inducible modulator of neurodegeneration. VHP-1 regulates the transcriptional response to mechanical stress and is itself attenuated by KGB-1-mediated inactivation of a deubiquitinase, MATH-33, and proteasomal degradation. Together, we describe an uncharacterized stress response pathway in C. elegans and identify transcriptional and post-translational components comprising a feedback loop on Jun kinase and phosphatase activity.
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http://dx.doi.org/10.1038/s41467-021-21611-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935884PMC
March 2021

Zmat3 Is a Key Splicing Regulator in the p53 Tumor Suppression Program.

Mol Cell 2020 11;80(3):452-469.e9

Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

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 in vivo. 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 Kras-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.
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http://dx.doi.org/10.1016/j.molcel.2020.10.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654708PMC
November 2020

Age-Onset Phosphorylation of a Minor Actin Variant Promotes Intestinal Barrier Dysfunction.

Dev Cell 2019 12;51(5):587-601.e7

Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

Age-associated decay of intercellular interactions impairs the cells' capacity to tightly associate within tissues and form a functional barrier. This barrier dysfunction compromises organ physiology and contributes to systemic failure. The actin cytoskeleton represents a key determinant in maintaining tissue architecture. Yet, it is unclear how age disrupts the actin cytoskeleton and how this, in turn, promotes mortality. Here, we show that an uncharacterized phosphorylation of a low-abundant actin variant, ACT-5, compromises integrity of the C. elegans intestinal barrier and accelerates pathogenesis. Age-related loss of the heat-shock transcription factor, HSF-1, disrupts the JUN kinase and protein phosphatase I equilibrium which increases ACT-5 phosphorylation within its troponin binding site. Phosphorylated ACT-5 accelerates decay of the intestinal subapical terminal web and impairs its interactions with cell junctions. This compromises barrier integrity, promotes pathogenesis, and drives mortality. Thus, we provide the molecular mechanism by which age-associated loss of specialized actin networks impacts tissue integrity.
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http://dx.doi.org/10.1016/j.devcel.2019.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897307PMC
December 2019

The Spatiotemporal Pattern and Intensity of p53 Activation Dictates Phenotypic Diversity in p53-Driven Developmental Syndromes.

Dev Cell 2019 07 6;50(2):212-228.e6. Epub 2019 Jun 6.

Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

Inappropriate activation of the p53 transcription factor contributes to numerous developmental syndromes characterized by distinct constellations of phenotypes. How p53 drives exquisitely specific sets of symptoms in diverse syndromes, however, remains enigmatic. Here, we deconvolute the basis of p53-driven developmental syndromes by leveraging an array of mouse strains to modulate the spatial expression pattern, temporal profile, and magnitude of p53 activation during embryogenesis. We demonstrate that inappropriate p53 activation in the neural crest, facial ectoderm, anterior heart field, and endothelium induces distinct spectra of phenotypes. Moreover, altering the timing and degree of p53 hyperactivation substantially affects the phenotypic outcomes. Phenotypes are associated with p53-driven cell-cycle arrest or apoptosis, depending on the cell type, with gene expression programs, rather than extent of mitochondrial priming, largely governing the specific response. Together, our findings provide a critical framework for decoding the role of p53 as a mediator of diverse developmental syndromes.
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http://dx.doi.org/10.1016/j.devcel.2019.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650355PMC
July 2019

Anesthetic and obstetric outcomes in pregnant women undergoing cesarean delivery according to body mass index: Retrospective analysis of a single-center experience.

Ann Med Surg (Lond) 2018 Dec 2;36:129-134. Epub 2018 Nov 2.

Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia at Augusta University, USA.

Aim: To evaluate maternal, neonatal and anesthetic outcomes according to BMI in women undergoing cesarean section.

Background: Increased incidence rates of obesity and morbid obesity have been reported in the United States. Pregnant obese patients are at increased risk of maternal and fetal complications, and obstetric and anesthetic management of these patients is especially challenging.

Methods: A retrospective chart review of patients who underwent cesarean section in a single center between 2015 and 2016 was conducted. Anesthetic, obstetric and neonatal outcomes were analyzed in relation to levels of BMI.

Results: Seven hundred and seventy one patients underwent cesarean section during the study period. The number of patients with normal BMI, obesity and morbid obesity was 213 (27.6%), 365 (47.3%) and 193 (25%), respectively. Sixty-one percent of the patients in morbidly obese group had at least one comorbidity (p < 0.01). We found no significant differences with respect to perioperative obstetric complications. Intraoperative blood loss was significantly higher in the morbidly obese group.

Conclusion: Increasing BMI is associated with comorbidities such as hypertension and diabetes mellitus, and with increased intraoperative blood loss. We were unable to detect differences in other obstetric, anesthetic and neonatal outcomes.
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http://dx.doi.org/10.1016/j.amsu.2018.10.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234280PMC
December 2018

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer.

Cancer Cell 2017 10;32(4):460-473.e6

Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

The p53 transcription factor is a critical barrier to pancreatic cancer progression. To unravel mechanisms of p53-mediated tumor suppression, which have remained elusive, we analyzed pancreatic cancer development in mice expressing p53 transcriptional activation domain (TAD) mutants. Surprisingly, the p53 TAD2 mutant behaves as a "super-tumor suppressor," with an enhanced capacity to both suppress pancreatic cancer and transactivate select p53 target genes, including Ptpn14. Ptpn14 encodes a negative regulator of the Yap oncoprotein and is necessary and sufficient for pancreatic cancer suppression, like p53. We show that p53 deficiency promotes Yap signaling and that PTPN14 and TP53 mutations are mutually exclusive in human cancers. These studies uncover a p53-Ptpn14-Yap pathway that is integral to p53-mediated tumor suppression.
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http://dx.doi.org/10.1016/j.ccell.2017.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659188PMC
October 2017
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