Cell and Developmental Biology Commons^™

Role Of Human Intermediate Form Prl Receptor I-Tail In The Pathogenesis Of Breast Cancer, Shanwei Shen

Theses and Dissertations

Breast cancer continues to be the second most common cancer in women in the United States. The neuroendocrine hormone human prolactin (hPRL) plays an important role in normal mammary gland development and growth, stimulating normal breast tissue proliferation and differentiation. Considerable evidence has shown that hPRL is involved in the malignant transformation of human breast tissue. hPRL enhances viability, invasiveness, and proliferation of breast cancer cells in vitro. Evidence from epidemiologic and genetic studies also implicates role of hPRL in the pathogenesis of breast cancer. Its cognate receptor the human prolactin receptor (hPRLr) is required for the action of hPRL. …

The Carboxy Terminus Causes Interfacial Assembly Of Oleate Hydratase On A Membrane Bilayer, Christopher D. Radka, Christy R. Grace, Hale S. Hasdemir, Yupeng Li, Carlos C. Rodriguez, Patrick Rodrigues, Michael L. Oldham, M. Zuhaib Qayyum, Aaron Pitre, William J. Maccain, Ravi C. Kalathur, Emad Tajkhorshid, Charles O. Rock

Markey Cancer Center Faculty Publications

The soluble flavoprotein oleate hydratase (OhyA) hydrates the 9-cis double bond of unsaturated fatty acids. OhyA sub- strates are embedded in membrane bilayers; OhyA must remove the fatty acid from the bilayer and enclose it in the active site. Here, we show that the positively charged helix- turn-helix motif in the carboxy terminus (CTD) is responsible for interacting with the negatively charged phosphatidylgly- cerol (PG) bilayer. Super-resolution microscopy of Staphylo- coccus aureus cells expressing green fluorescent protein fused to OhyA or the CTD sequence shows subcellular localization along the cellular boundary, indicating OhyA is membrane- associated and the CTD sequence …

Elevated Free Cholesterol Levels Due To Impaired Reverse Cholesterol Transport Are A Risk Factor For Polymicrobial Sepsis In Mice, Qian Wang, Ling Guo, Dan Hao, Misa Ito, Chieko Mineo, Philip W. Shaul, Xiang-An Li

Markey Cancer Center Faculty Publications

Dysregulated lipid metabolism is commonly observed in septic patients, but how it contributes to sepsis remains largely unknown. Reverse cholesterol transport (RCT) is crucial for regulating cholesterol metabolism in circulation. During RCT, high-density lipoprotein collects cholesterol from peripheral tissues and transports it to the liver’s scavenger receptor BI (SR- BI), where SR-BI mediates the uptake of cholesteryl esters (CEs) from high-density lipoprotein for excretion via bile. In this study, we utilized AlbCreSR-BIfl/fl mice, a model with impaired RCT, to investigate the impact of RCT on sepsis. We found that AlbCreSR-BIfl/fl mice were significantly more susceptible to cecal ligation and puncture …

Nudcl2 Is Required For Cytokinesis By Stabilizing Rcc2 With Hsp90 At The Midbody, Xiaoyang Xu, Yuliang Huang, Feng Yang, Xiaoxia Sun, Rijin Lin, Jiaxing Feng, Mingyang Yang, Jiaqi Shao, Xiaoqi Liu, Tianhua Zhou, Shanshan Xie, Yuehong Yang

Markey Cancer Center Faculty Publications

Cytokinesis is required for faithful division of cytoplasmic components and duplicated nuclei into two daughter cells. Midbody, a protein-dense organelle that forms at the intercellular bridge, is indispensable for success- ful cytokinesis. However, the regulatory mechanism of cytokinesis at the midbody still remains elusive. Here, we unveil a critical role for NudC-like protein 2 (NudCL2), a co-chaperone of heat shock protein 90 (Hsp90), in cytokinesis regulation by stabilizing regulator of chromosome condensation 2 (RCC2) at the midbody in mam- malian cells. NudCL2 localizes at the midbody, and its downregulation results in cytokinesis failure, multinu- cleation, and midbody disorganization. Using iTRAQ-based …

Pai-1 As A Critical Factor In The Resolution Of Sepsis And Acute Kidney Injury In Old Age, Maria E. C. Bruno, Sujata Mukherjee, Jamie L. Sturgill, Virgilius Cornea, Peng Yeh, Gregory S. Hawk, Hiroshi Saito, Marlene E. Starr

Markey Cancer Center Faculty Publications

Elevated plasma levels of plasminogen activator inhibitor type 1 (PAI-1) are documented in patients with sepsis and levels positively correlate with disease severity and mortality. Our prior work demonstrated that PAI-1 in plasma is positively associated with acute kidney injury (AKI) in septic patients and mice. The objective of this study was to determine if PAI-1 is causally related to AKI and worse sepsis outcomes using a clinically-relevant and age-appropriate murine model of sepsis. Sepsis was induced by cecal slurry (CS)-injection to wild-type (WT, C57BL/6) and PAI-1 knockout (KO) mice at young (5–9 months) and old (18–22 months) age. Survival …

Structure, Dynamics, And Redox Reactivity Of An All-Purpose Flavodoxin, Sharique Khan, Ahmadullah Ansari, Monica Brachi, Debarati Das, Wassim El Housseini, Shelley Minteer, Anne-Francis Miller

Markey Cancer Center Faculty Publications

The flavodoxin of Rhodopseudomonas palustris CGA009 (Rp9Fld) supplies highly reducing equivalents to crucial en- zymes such as hydrogenase, especially when the organism is iron-restricted. By acquiring those electrons from photodriven electron flow via the bifurcating electron transfer flavoprotein, Rp9Fld provides solar power to vital metabolic processes. To understand Rp9Fld’s ability to work with diverse partners, we solved its crystal structure. We observed the canonical fla- vodoxin (Fld) fold and features common to other long-chain Flds but not all the surface loops thought to recognize part- ner proteins. Moreover, some of the loops display alternative structures and dynamics. To advance studies …

Non-Transcriptional Irf7 Interacts With Nf-Κb To Inhibit Viral Inflammation, Shumin Fan, Sonam Popli, Sukanya Chakravarty, Ritu Chakravarty, Saurabh Chattopadhyay

Markey Cancer Center Faculty Publications

Interferon (IFN) regulatory factors (IRF) are key transcrip- tion factors in cellular antiviral responses. IRF7, a virus- inducible IRF, expressed primarily in myeloid cells, is required for transcriptional induction of interferon α and antiviral genes. IRF7 is activated by virus-induced phosphory- lation in the cytoplasm, leading to its translocation to the nu- cleus for transcriptional activity. Here, we revealed a nontranscriptional activity of IRF7 contributing to its antiviral functions. IRF7 interacted with the pro-inflammatory tran- scription factor NF-κB-p65 and inhibited the induction of in- flammatory target genes. Using knockdown, knockout, and overexpression strategies, we demonstrated that IRF7 inhibited NF-κB–dependent inflammatory …

Foxs1 Is Increased In Liver Fibrosis And Regulates Tgfβ Responsiveness And Proliferation Pathways In Human Hepatic Stellate Cells, Evelyn A. Bates, Zachary A. Kipp, Wang-Hsin Lee, Genesee J. Martinez, Lauren Weaver, Kathryn N. Becker, Sally Pauss, Justin F. Creeden, Garrett B. Anspach, Robert N. Helsley, Mei Xu, Maria E. C. Bruno, Marlene E. Starr, Terry D. Hinds Jr.

Markey Cancer Center Faculty Publications

Liver fibrosis commences with liver injury stimulating transforming growth factor beta (TGFβ) activation of hepatic stellate cells (HSCs), causing scarring and irreversible damage. TGFβ induces expression of the transcription factor Forkhead box S1 (FOXS1) in hepatocytes and may have a role in the pathogenesis of hepatocellular carcinoma (HCC). To date, no studies have determined how it affects HSCs. We analyzed human livers with cirrhosis, HCC, and a murine fibrosis model and found that FOXS1 expression is significantly higher in fibrotic livers but not in HCC. Next, we treated human LX2 HSC cells with TGFβ to activate fibrotic pathways, and FOXS1 …

Mir-27a-3p Regulates Intestinal Cell Proliferation And Differentiation Through Wnt/Β-Catenin Signalling, Chang Li, Yuning Zhou, Yinping Jiang, Zhijie Yin, Heidi L. Weiss, Qingding Wang, B. Mark Evers

Markey Cancer Center Faculty Publications

Intestinal stem cells differentiate into absorptive enterocytes, characterised by increased brush border enzymes such as intestinal alkaline phosphatase (IAP), making up the majority (95%) of the terminally differentiated cells in the villus. Loss of integ- rity of the intestinal epithelium plays a key role in inflammatory diseases and gastro- intestinal infection. Here, we show that the intestinal microRNA (miR)-27a-3p is an important regulator of intestinal epithelial cell proliferation and enterocyte differenti- ation. Repression of endogenous miR-27a-3p leads to increased enterocyte differen- tiation and decreased intestinal epithelial cell proliferation in mouse and human small intestinal organoids. Mechanistically, miR-27a-3p regulates intestinal cell …

Nanotoxicology Of Cdse/Zns Quantum Dot Alternatives In Thle-2 And Hepg2 Liver Cells, Seth Harris

Graduate Theses/Dissertations

Fluorescent nanoparticles known as quantum dots (QDs) have unique properties that make them useful in biomedicine. Specifically, CdSe/ZnS QDs, while good at fluorescing, show toxicity. Due to this, safer alternatives have been developed. This study uses an XTT viability assay, ROS fluorescent imaging, and apoptosis to investigate the effect of QD alternatives InP/ZnS, CuInS₂/ZnS, and carbon dots (NCD) in liver cells. The liver is a possible destination for accumulation of QDs making it an appropriate model for testing. A cancerous liver cell line known as HepG2, and an immortalized liver cell line known as THLE-2 were used. At …

Tim/Tam Receptors: A Potential Biomarker For Predicting Sensitivity To Zika Virus-Induced Oncolysis In Non-Small Cell Lung Cancers, Shankari Somasekar

Honors Undergraduate Theses

Non-small cell lung cancers (NSCLC) constitute 80-85% of lung cancers and are the leading cause of cancer-related deaths globally. The most common cause is prolonged smoking. Current treatment options for NSCLC include surgery, radiation, chemotherapy, targeted drug therapy, and immunotherapy. Although these medications are effective in the short term, patients often face issues of drug resistance and debilitating side effects with prolonged use. Currently, the use of Zika virus (ZIKV) is being researched as a possible alternative treatment for cancer, which minimizes side effects and the risk of drug resistance. TIM/TAM proteins are identified as the putative ZIKV receptors on …

Methylene Blue-Mediated Photodynamic Therapy In Combination With Doxorubicin: A Novel Approach In The Treatment Of Ht-29 Colon Cancer Cells, Nima Rastegar-Pouyani, Jaber Zafari, Alireza Nasirpour, Hossein Vazini, Nabbaa Najjar, Seyedeh Zohreh Azarshin, Fatemeh Javani Jouni

Electrical & Computer Engineering Faculty Publications

Introduction: With an alarmingly growing number of patients diagnosed with colorectal cancer, adopting innovative anti-cancer approaches has recently garnered great attention. One interesting concept is the co-administration of cytotoxic agents and safer modalities such as photodynamic therapy (PDT), which can subsequently improve therapeutic efficacy and potentially reduce the risks of severe adverse effects and drug resistance. In the course of PDT, a locally injected photosensitizer (PS) is irradiated with a light source, which subsequently generates reactive oxygen species (ROS) and induces programmed cell death in tumor cells.

Methods: In this study, to evaluate the potential anti-cancer effects of chemotherapy combined …

A Scoping Review Of Population Diversity In The Common Genomic Aberrations Of Clear Cell Renal Cell Carcinoma, Sean S. Kumar, Ninad Khandekar, Komal Dani, Saina R. Bhatt, Vinay Duddalwar, Anishka D'Souza

Department of Medicine Faculty Publications

Introduction: Previous literature has shown that clear cell renal cell carcinoma (ccRCC) is becoming a more prevalent diagnosis and that the incidence and mortality differ both regionally and racially. While the molecular profiles for ccRCC are studied regionally through biopsy and sequencing techniques, the genomic landscape and ccRCC diversity data are not well-studied. We conducted a review of the known genomic data on 6 of the most clinically relevant DNA biomarkers in ccRCC: Von Hippel-Landau (vHL), Polybromo-1 (PBRM1), Breast Cancer Gene 1-Associated Protein 1 (BAP1), Histone-Lysine N-Methyltransferase Domain-Containing 2 (SETD2), Mammalian Target of Rapamycin (mTOR), and Lysine-Specific Demethylase 5C (KDM5C). …

Paper-Based Dna Biosensor For Rapid And Selective Detection Of Mir-21, Alexander Hunt, Sri Ramulu Torati, Gymama Slaughter

Electrical & Computer Engineering Faculty Publications

Cancer is the second leading cause of death globally, with 9.7 million fatalities in 2022. While routine screenings are vital for early detection, healthcare disparities persist, highlighting the need for equitable solutions. Recent advancements in cancer biomarker identification, particularly microRNAs (miRs), have improved early detection. MiR-21 is notably overexpressed in various cancers and can be a valuable diagnostic tool. Traditional detection methods, though accurate, are costly and complex, limiting their use in resource-limited settings. Paper-based electrochemical biosensors offer a promising alternative, providing cost-effective, sensitive, and rapid diagnostics suitable for point-of-care use. This study introduces an innovative electrochemical paper-based biosensor that …

Sccad: Cluster Decomposition-Based Anomaly Detection For Rare Cell Identification In Single-Cell Expression Data, Yunpei Xu, Shaokai Wang, Qilong Feng, Jiazhi Xia, Yaohang Li, Hong-Dong Li, Jianxin Wang

Computer Science Faculty Publications

Single-cell RNA sequencing (scRNA-seq) technologies have become essential tools for characterizing cellular landscapes within complex tissues. Large-scale single-cell transcriptomics holds great potential for identifying rare cell types critical to the pathogenesis of diseases and biological processes. Existing methods for identifying rare cell types often rely on one-time clustering using partial or global gene expression. However, these rare cell types may be overlooked during the clustering phase, posing challenges for their accurate identification. In this paper, we propose a Cluster decomposition-based Anomaly Detection method (scCAD), which iteratively decomposes clusters based on the most differential signals in each cluster to effectively separate …

Triphlapan: Predicting Hla Molecules Binding Peptides Based On Triple Coding Matrix And Transfer Learning, Meng Wang, Chuqi Lei, Jianxin Wang, Yaohang Li, Min Li

Computer Science Faculty Publications

Human leukocyte antigen (HLA) recognizes foreign threats and triggers immune responses by presenting peptides to T cells. Computationally modeling the binding patterns between peptide and HLA is very important for the development of tumor vaccines. However, it is still a big challenge to accurately predict HLA molecules binding peptides. In this paper, we develop a new model TripHLApan for predicting HLA molecules binding peptides by integrating triple coding matrix, BiGRU + Attention models, and transfer learning strategy. We have found the main interaction site regions between HLA molecules and peptides, as well as the correlation between HLA encoding and binding …

Elucidating Mechanisms Of Enhanced Dsrna-Nanophytoglycogen Innate Immune Responses In Healthy Human Cells, Nicholas Jadaa

Theses and Dissertations (Comprehensive)

Immunostimulatory nucleic acids, such as long double-stranded RNA (ds)RNA, can stimulate innate immune responses in a non-sequence specific manner. These molecules are recognized by pattern-recognition receptors in the cytoplasm, endosome, and on the cell surface. Activation leads to the production of mediators of innate immune pathways, including type I interferon and proinflammatory cytokines. Although these receptors are present in all cells, their role in non-immune cells is often overlooked due to their lower level of responsiveness. Nanocarriers can enhance these nucleic acid-mediated responses, allowing for exploration of innate immune pathways in non-immune cells. Nanoparticles as carriers of nucleic acids can …

Developing Cellular Systems To Elucidate Rna Structural Dynamics Of Cag Expansion Transcripts In Spinocerebellar Ataxias, Victoria Demeo

Electronic Theses & Dissertations (2024 - present)

Spinocerebellar ataxias (SCAs) are a diverse group of over 40 genetically heterogeneous neurodegenerative disorders, many of which are caused by a trinucleotide CAG repeat expansion in the coding region of specific genes. These expansions lead to the production of polyglutamine (polyQ) tracts that interfere with normal protein function, triggering cellular dysfunction and contributing to disease pathogenesis. The most well-known of these SCAs, such as SCA1, SCA2, and SCA3, exhibit progressive neurodegeneration, yet the precise mechanisms through which these mutations cause disease remain poorly understood.

A significant challenge in studying CAG repeat expansion disorders lies in the complexity of the disease …

Chromatin Regulation By Swi/Snf Remodelers In Somatic Stem Cell Maintenance And Transformation, Luke Thomas Deary

Dartmouth College Ph.D Dissertations

Cell identity is defined by the epigenome, whereby chromatin regulators work in concert to promote gene expression programs that serve a cell’s specialized purpose. Mutations in chromatin regulators are amongst the most frequent drivers of human disease, underscoring the importance of understanding their activities in maintaining cell identity and tissue function. In particular, mutations in subunits of the evolutionarily conserved SWI/SNF chromatin remodeling complexes drive diseases across human tissues in both development and adult tissue maintenance5. Three major SWI/SNF complexes exist: BAF, PBAF, and GBAF, which differ in their composition and genomic targeting but share an ATP-dependent catalytic activity to …

Near-Infrared Paired-Agent Imaging For In Vivo Quantification Of Receptor Occupancy In Tumor, Yichen Feng

Dartmouth College Ph.D Dissertations

Accurate assessment of drug receptor occupancy (RO) holds significant importance in both drug development and personalized medicine, as it facilitates quantitative characterization of dose-response relationship for a given drug. This information not only aids appropriate dose selection for clinical trials but also guides personalized dose optimization in precision medicine.

Molecular imaging, utilizing receptor-specific imaging agents for tissue visualization, has emerged as the major option for in vivo measurement of tissue RO. Nonetheless, the abnormal yet complex structure and hemodynamics of tumors often lead to substantial non-specific uptake and retention of imaging agents, thus introducing significant bias to RO measurements. To …

Neurodevelopmental Vulnerability To Gestational Ozone Exposure, Vishnupriya Alavala, Sarah E. Brent, Christopher G. Canal, Joseph Wang, Russell P. Hunter, Matthew J. Campen, Andrew K. Ottens

Undergraduate Research Posters

Ambient air pollution accounts for about 4.2 million premature deaths annually per the World Health Organization. Ozone (O3) is a highly reactive air pollutant found in smog and is implicated in cellular damage leading to organ dysfunction. Ambient air pollution is associated with neurodevelopmental, behavioral, and cognitive disorders though ozone’s role is unknown. Studies here look at ozone exposure shortly after implantation vs. shortly before term to evaluate differences in neurodevelopmental susceptibility over time.

To inquire on the effects of ozone on the fetal brain, pregnant Sprague-Dawley rats were exposed once to 0.3 ppm of O3 or filtered air (FA) …

27-Hydroxycholesterol And Dna Damage Repair: Implication In Prostate Cancer, Gloria Cecilia Galvan, Nadine Friedrich, Sanjay Das, James Daniels, Sara Pollan, Shweta Dambal, Ryusuke Suzuki, Sergio Sanders, Sungyong You, Hisashi Tanaka, Yeon-Joo Lee, Wei Yuan, Johann De Bono, Irina Vasilevskaya, Karen Knudsen, Michael Freeman, Stephen Freedland

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

INTRODUCTION: We previously reported that cholesterol homeostasis in prostate cancer (PC) is regulated by 27-hydroxycholesterol (27HC) and that CYP27A1, the enzyme that converts cholesterol to 27HC, is frequently lost in PCs. We observed that restoring the CYP27A1/27HC axis inhibited PC growth. In this study, we investigated the mechanism of 27HC-mediated anti-PC effects.

METHODS: We employed in vitro models and human transcriptomics data to investigate 27HC mechanism of action in PC. LNCaP (AR+) and DU145 (AR-) cells were treated with 27HC or vehicle. Transcriptome profiling was performed using the Affymetrix GeneChip™ microarray system. Differential expression was determined, and gene set enrichment …

Needle Biopsy Accelerates Pro-Metastatic Changes And Systemic Dissemination In Breast Cancer: Implications For Mortality By Surgery Delay, Hiroyasu Kameyama, Priya Dondapati, Reese Simmons, Macall Leslie, John Langenheim, Yunguang Sun, Misung Yi, Aubrey Rottschaefer, Rashmi Pathak, Shreya Nuguri, Kar-Ming Fung, Shirng-Wern Tsaih, Inna Chervoneva, Hallgeir Rui, Takemi Tanaka

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

ncreased breast cancer (BC) mortality risk posed by delayed surgical resection of tumor after diagnosis is a growing concern, yet the underlying mechanisms remain unknown. Our cohort analyses of early-stage BC patients reveal the emergence of a significantly rising mortality risk when the biopsy-to-surgery interval was extended beyond 53 days. Additionally, histology of post-biopsy tumors shows prolonged retention of a metastasis-permissive wound stroma dominated by M2-like macrophages capable of promoting cancer cell epithelial-to-mesenchymal transition and angiogenesis. We show that needle biopsy promotes systemic dissemination of cancer cells through a mechanism of sustained activation of the COX-2/PGE₂/EP2 feedforward loop, …

Nucleus Accumbens Core Single Cell Ensembles Bidirectionally Respond To Experienced Versus Observed Aversive Events, Oyku Dinckol, Noah Harris Wenger, Jennifer E Zachry, Munir Gunes Kutlu

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Fear learning is a critical feature of survival skills among mammals. In rodents, fear learning manifests itself through direct experience of the aversive event or social transmission of aversive stimuli such as observing and acting on conspecifics' distress. The neuronal network underlying the social transmission of information largely overlaps with the brain regions that mediate behavioral responses to aversive and rewarding stimuli. In this study, we recorded single cell activity patterns of nucleus accumbens (NAc) core neurons using in vivo optical imaging of calcium transients via miniature scopes. This cutting-edge imaging methodology not only allows us to record activity patterns …

Air-Jet Bioprinting Of Stem Cell-Encapsulated Alginate Micro-Droplets For Organoid Biomanufacturing, Mirabella B. Stump

Electronic Theses and Dissertations

Biomanufactured 3D-organoids show promise for modeling and treating various conditions, particularly insulin-dependent diabetes mellitus (type-1 diabetes). Pancreatic islet organoids serve as sustainable sources of insulin-producing β-cells, potentially restoring insulin regulation in patients and providing a long-term solution for diabetes. Hydrogel droplet printing is an emerging technique in regenerative medicine due to its advantageous tunability and biocompatibility; however, challenges of consistency, quality control, and scalability persist. To address these issues, we developed a novel air-jetting based droplet bioprinting system for the generation of monodispersed alginate micro-droplets. The objective of this project was to incorporate human induced pluripotent stem cells (hiPSCs) into …

Role Of Gonadotropin-Releasing Hormone 2 And Its Receptor In Human Reproductive Cancers, Dr. Amy T. Desaulniers, Brett White

School of Veterinary and Biomedical Sciences: Faculty Publications

Gonadotropin-releasing hormone (GnRH1) and its receptor (GnRHR1) drive reproduction by regulating gonadotropins. Another form, GnRH2, and its receptor (GnRHR2), also exist in mammals. In humans, GnRH2 and GnRHR2 genes are present, but coding errors in the GnRHR2 gene are predicted to hinder full-length protein production. Nonetheless, mounting evidence supports the presence of a functional GnRHR2 in humans. GnRH2 and its receptor have been identified throughout the body, including peripheral reproductive tissues like the ovary, uterus, breast, and prostate. In addition, GnRH2 and its receptor have been detected in a wide number of reproductive cancer cells in humans. Notably, GnRH2 analogues …

Pediatric Parosteal Osteosarcoma Of The Distal Radius Causing Extensive Erosive Mass Effect Of The Adjacent Ulna: A Case Report, Andrea Perloff, Sehoon Park, Robert Panganiban, John Devries

Department of Orthopaedics Faculty Research

Introduction: Parosteal osteosarcomas are low-grade bony malignancies that are treated primarily with surgical resection and reconstruction. This report discusses a unique case of a pediatric patient who presented with a parosteal osteosarcoma of the distal radius causing extensive erosive mass effect and growth disturbance of the adjacent ulna. Likely due to their slow-growing nonaggressive nature, parosteal osteosarcomas have not been previously described to abut adjacent bony structures through direct contact. The patient presented in a significantly delayed manner due to social circumstances, inadvertently revealing this novel behavior. This report reviews this rare case and describes the current understanding of this …

Phi-1, An Endogenous Inhibitor Protein For Protein Phosphatase-1 And A Pan-Cancer Marker, Regulates Raf-1 Proteostasis, Jason Kirkbride, Garbo Nilsson, Jee In Kim, Kosuke Takeya, Yoshinori Tanaka, Hiroshi Tokumitsu, Futoshi Suizu, Masumi Eto

Kimmel Cancer Center Faculty Papers

Raf-1, a multifunctional kinase, regulates various cellular processes, including cell proliferation, apoptosis, and migration, by phosphorylating MAPK/ERK kinase and interacting with specific kinases. Cellular Raf-1 activity is intricately regulated through pathways involving the binding of regulatory proteins, direct phosphorylation, and the ubiquitin-proteasome axis. In this study, we demonstrate that PHI-1, an endogenous inhibitor of protein phosphatase-1 (PP1), plays a pivotal role in modulating Raf-1 proteostasis within cells. Knocking down endogenous PHI-1 in HEK293 cells using siRNA resulted in increased cell proliferation and reduced apoptosis. This heightened cell proliferation was accompanied by a 15-fold increase in ERK1/2 phosphorylation. Importantly, the observed …

Design Of An Fgf-1-Fgf-2 Heterodimer Variant With Enhanced Stability And Cell Proliferation Activity, Nicholas Alan Pohlman

Chemistry & Biochemistry Undergraduate Honors Theses

The FGF-1 subfamily, composed of FGF-1 and FGF-2, assists in broad health-related processes such as cell proliferation and angiogenesis respectively.^1,2 The subfamily shows promising signs as a therapeutic, however, the inherent thermal instability leads to a low half-life in vivo.³ To assist in improving the stability, FGF-1 and FGF-2 were connected via a 12-residue glycine linker ultimately producing a heterodimer. This heterodimer was further examined to discover its novel properties. Inspiration for this project was drawn from previous research which performed five mutations on FGF-1 ultimately improving stability in the protein complex. In addition to these five …

Cell Aggregation Activates Small Gtpase Rac1 And Induces Cd44 Cleavage By Maintaining Lipid Raft Integrity, Dong Li, Younhee Park, Hami Hemati, Xia Liu

Markey Cancer Center Faculty Publications

Lipid rafts are highly ordered membrane domains that are enriched in cholesterol and glycosphingolipids and serve as major platforms for signal transduction. Cell detachment from the extracellular matrix (ECM) triggers lipid raft disruption and anoikis, which is a barrier for cancer cells to metastasize. Compared to single circulating tumor cells (CTCs), our recent studies have demonstrated that CD44-mediatd cell aggregation enhances the stemness, survival and metastatic ability of aggregated cells. Here, we investigated whether and how lipid rafts are involved in CD44-mediated cell aggregation. We found that cell detachment, which mimics the condition when tumor cells detach from the ECM …