Medical Sciences Commons^™

Natural And Induced Mitochondrial Phosphate Carrier Loss: Differential Dependence Of Mitochondrial Metabolism And Dynamics And Cell Survival On The Extent Of Depletion., Erin L. Seifert, Aniko Gál, Michelle G. Acoba, Qipei Li, Lauren Anderson-Pullinger, Tünde Golenár, Cynthia Moffat, Neal Sondheimer, Steven M. Claypool, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The relevance of mitochondrial phosphate carrier (PiC), encoded by SLC25A3, in bioenergetics is well accepted. However, little is known about the mechanisms mediating the cellular impairments induced by pathological SLC25A3 variants. To this end, we investigated the pathogenicity of a novel compound heterozygous mutation in SLC25A3 First, each variant was modeled in yeast, revealing that substituting GSSAS for QIP within the fifth matrix loop is incompatible with survival on non-fermentable substrate, whereas the L200W variant is functionally neutral. Next, using skin fibroblasts from an individual expressing these variants and HeLa cells with varying degrees of PiC depletion, PiC loss of …

Single-Cell Transcriptional Analysis Reveals Novel Neuronal Phenotypes And Interaction Networks Involved In The Central Circadian Clock., James Park, Haisun Zhu, Sean O'Sullivan, Babatunde A Ogunnaike, David R Weaver, James S. Schwaber, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Single-cell heterogeneity confounds efforts to understand how a population of cells organizes into cellular networks that underlie tissue-level function. This complexity is prominent in the mammalian suprachiasmatic nucleus (SCN). Here, individual neurons exhibit a remarkable amount of asynchronous behavior and transcriptional heterogeneity. However, SCN neurons are able to generate precisely coordinated synaptic and molecular outputs that synchronize the body to a common circadian cycle by organizing into cellular networks. To understand this emergent cellular network property, it is important to reconcile single-neuron heterogeneity with network organization. In light of recent studies suggesting that transcriptionally heterogeneous cells organize into distinct cellular …

Mirna-145 Increases Therapeutic Sensibility To Gemcitabine Treatment Of Pancreatic Adenocarcinoma Cells., Yong Lin, Xin Ge, Yiyang Wen, Zhu-Mei Shi, Qiu-Dan Chen, Min Wang, Ling-Zhi Liu, Bing-Hua Jiang, Yuan Lu

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Pancreatic adenocarcinoma is one of the most leading causes of cancer-related deaths worldwide. Although recent advances provide various treatment options, pancreatic adenocarcinoma has poor prognosis due to its late diagnosis and ineffective therapeutic multimodality. Gemcitabine is the effective first-line drug in pancreatic adenocarcinoma treatment. However, gemcitabine chemoresistance of pancreatic adenocarcinoma cells has been a major obstacle for limiting its treatment effect. Our study found that p70S6K1 plays an important role in gemcitabine chemoresistence. MiR-145 is a tumor suppressor which directly targets p70S6K1 for inhibiting its expression in pancreatic adenocarcinoma, providing new therapeutic scheme. Our findings revealed a new mechanism underlying …

Integrated Live Imaging And Molecular Profiling Of Embryoid Bodies Reveals A Synchronized Progression Of Early Differentiation., Jonathan Boxman, Naor Sagy, Sirisha Achanta, Rajanikanth Vadigepalli, Iftach Nachman

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Embryonic stem cells can spontaneously differentiate into cell types of all germ layers within embryoid bodies (EBs) in a highly variable manner. Whether there exists an intrinsic differentiation program common to all EBs is unknown. Here, we present a novel combination of high-throughput live two-photon imaging and gene expression profiling to study early differentiation dynamics spontaneously occurring within developing EBs. Onset timing of Brachyury-GFP was highly variable across EBs, while the spatial patterns as well as the dynamics of mesendodermal progression following onset were remarkably similar. We therefore defined a 'developmental clock' using the Brachyury-GFP signal onset timing. Mapping snapshot …

The Structure And Regulation Of Cullin 2 Based E3 Ubiquitin Ligases And Their Biological Functions., Weijia Cai, Haifeng Yang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Cullin-RING E3 ubiquitin ligase complexes play a central role in targeting cellular proteins for ubiquitination-dependent protein turnover through 26S proteasome. Cullin-2 is a member of the Cullin family, and it serves as a scaffold protein for Elongin B and C, Rbx1 and various substrate recognition receptors to form E3 ubiquitin ligases.

MAIN BODY OF THE ABSTRACT: First, the composition, structure and the regulation of Cullin-2 based E3 ubiquitin ligases were introduced. Then the targets, the biological functions of complexes that use VHL, Lrr-1, Fem1b, Prame, Zyg-11, BAF250, Rack1 as substrate targeting subunits were described, and their involvement in diseases …

Micu1 Regulation Of Mitochondrial Ca(2+) Uptake Dictates Survival And Tissue Regeneration., Anil Noronha Antony, Melanie Paillard, Cynthia Moffat, Egle Juskeviciute, Jason Correnti, Brad Bolon, Emanual Rubin, Md, György Csordás, Erin L Seifert, Jan B. Hoek, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Mitochondrial Ca(2+) uptake through the recently discovered Mitochondrial Calcium Uniporter (MCU) is controlled by its gatekeeper Mitochondrial Calcium Uptake 1 (MICU1). However, the physiological and pathological role of MICU1 remains unclear. Here we show that MICU1 is vital for adaptation to postnatal life and for tissue repair after injury. MICU1 knockout is perinatally lethal in mice without causing gross anatomical defects. We used liver regeneration after partial hepatectomy as a physiological stress response model. Upon MICU1 loss, early priming is unaffected, but the pro-inflammatory phase does not resolve and liver regeneration fails, with impaired cell cycle entry and extensive necrosis. …

Microrna Dysregulation And Esophageal Cancer Development Depend On The Extent Of Zinc Dietary Deficiency., Louise Fong, Cristian Taccioli, Ruiyan Jing, Karl Smalley, Hansjuerg Alder, Yubao Jiang, Paolo Fadda, John Farber, Carlo M Croce

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Zinc deficiency (ZD) increases the risk of esophageal squamous cell carcinoma (ESCC), and marginal ZD is prevalent in humans. In rats, marked-ZD (3 mg Zn/kg diet) induces a proliferative esophagus with a 5-microRNA signature (miR-31, -223, -21, -146b, -146a) and promotes ESCC. Here we report that moderate and mild-ZD (6 and 12 mg Zn/kg diet) also induced esophageal hyperplasia, albeit less pronounced than induced by marked-ZD, with a 2-microRNA signature (miR-31, -146a). On exposure to an environmental carcinogen, ~16% of moderate/mild-ZD rats developed ESCC, a cancer incidence significantly greater than for Zn-sufficient rats (0%) (P ≤ 0.05), but lower than …

Cells Activated For Wound Repair Have The Potential To Direct Collective Invasion Of An Epithelium., Brigid M Bleaken, A Sue Menko, Janice Walker

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Mechanisms regulating how groups of cells are signaled to move collectively from their original site and invade surrounding matrix are poorly understood. Here we develop a clinically relevant ex vivo injury invasion model to determine whether cells involved in directing wound healing have invasive function and whether they can act as leader cells to direct movement of a wounded epithelium through a three-dimensional (3D) extracellular matrix (ECM) environment. Similar to cancer invasion, we found that the injured cells invade into the ECM as cords, involving heterotypical cell-cell interactions. Mesenchymal cells with properties of activated repair cells that typically locate to …