Biochemistry, Biophysics, and Structural Biology Commons^™

Novel Roles Of Replication Protein A Phosphorylation In Cellular Response To Dna Damage, Moises A. Serrano

Electronic Theses and Dissertations

Human replication protein A (RPA) is an eukaryotic single-stranded DNA binding protein directly involved in a variety of DNA metabolic pathways including replication, recombination, DNA damage checkpoints and signaling, as well as all DNA repair pathways. This project presents 2 novel roles of RPA in the cellular response to DNA damage. The first elucidates the regulation of RPA and p53 interaction by DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) in homologous recombination (HR). HR and nonhomologous end joining (NHEJ) are 2 distinct DNA double-stranded break (DSB) repair pathways. Here, we report that DNA-PK, the …

Treating Cancer With Heat: Hyperthermia As Promising Strategy To Enhance Apoptosis, Kanwal Ahmed, Syed Faisal Zaidi

Department of Biological & Biomedical Sciences

The fundamental idea and the effects of heat on cancer cells are well known. However, the results obtained in therapy by hyperthermia (HT) alone have been only partially satisfactory. Treatment at temperatures between .40 and 44 degrees C is cytotoxic for cells in an environment with a low oxygen partial pressure and low pH, conditions that are found specifically within tumour tissue, due to insufficient blood perfusion. Under such conditions radiotherapy is less effective, and systemically applied cytotoxic agents will reach such areas in lower concentrations than in well-perfused areas. Therefore, clinically, it is preferred to use hyperthermia in combination …

Investigating The Effects Of Bag3 Knockdown On The Cytotoxicity Of The Anticancer Drug Laromustine, Kayla Gross

Honors Theses

Laromustine is a sulfonylhydrazine anticancer prodrug whose cytotoxicity results from the formation of interstrand cross-links caused by the synergistic action of co- generated 2-chloroethylating and carbamoylating species. The cytotoxic activities of Laromustine involve the induction of apoptosis. Described herein is an investigation into this drug’s effects on apoptotic gene expression in HL-60 cells using qRT-PCR. Significant changes in the expression levels of 13 genes were observed, most dramatically in the upregulation of the bcl2-associated athanogene 3 (BAG3) gene. Given the pro-survival role of BAG3 in the cell, this investigation sought to decrease BAG3 mRNA levels in HL-60 cells using transient …

Bovine Herpes Virus 1 (Bhv-1) And Herpes Simplex Virus Type 1 (Hsv-1) Promote Survival Of Latently Infected Sensory Neurons, In Part By Inhibiting Apoptosis, Clinton Jones

School of Veterinary and Biomedical Sciences: Faculty Publications

α-Herpesvirinae subfamily members, including herpes simplex virus type 1 (HSV-1) and bovine herpes virus 1 (BHV-1), initiate infection in mucosal surfaces. BHV-1 and HSV-1 enter sensory neurons by cell-cell spread where a burst of viral gene expression occurs. When compared to non-neuronal cells, viral gene expression is quickly extinguished in sensory neurons resulting in neuronal survival and latency. The HSV-1 latency associated transcript (LAT), which is abundantly expressed in latently infected neurons, inhibits apoptosis, viral transcription, and productive infection, and directly or indirectly enhances reactivation from latency in small animal models. Three anti-apoptosis genes can be substituted for LAT, which …

Effect Of Folate Deficiency And Aging On Mtor Signaling Network In The Liver Of Dna Polymerase B Haploinsufficient Mice, Amanda Lynn Arrabi

Wayne State University Theses

EFFECT OF FOLATE DEFICIENCY AND AGING ON mTOR SIGNALING NETWORK IN THE LIVER OF DNA POLYMERASE B HAPLOINSUFFICIENT MICE

by

AMANDA ARRABI

August 2013

Advisor: Dr. Ahmad R. Heydari

Major: Nutrition and Food Science

Degree: Masters of Science

The interaction between the dietary nutrients and the human genome causes some alterations in the molecular pathways that could significantly impact the development of cancer. The main approach to such concerns is to closely observe how the diet modifies the gene expressions that control several cellular processes in the human body. Folate deficiency (FD) has established an important role in modulating the …

Regulation Of The Tumor Suppresser P53 And Survivin By Ras And Ral Gtpases:Implications For Malignant Transformation, Awet G. Tecleab

USF Tampa Graduate Theses and Dissertations

Abstract

Although the critical role of the small GTPases Ras and Ral in oncogenesis has been well documented, much remains to be investigated about the molecular mechanism by which these GTPases regulate malignant transformation. The work under this thesis made two major contributions to this field. The first is the discovery that K-Ras, RalA and/or RalB are required for the maintenance of the high levels of the anti-apoptotic protein survivin in some human cancer cells, and the second is the demonstration that down regulation of K-Ras, RalA and/or RalB, but not Raf-1 or Akt1/2, stabilizes the tumor suppressor p53 and …

Biochemical And Cellular Mechanisms Of Retina And Retinal Pigment Epithelium Apoptosis, Srinivasa Rao Sripathi

Dissertations, Master's Theses and Master's Reports - Open

Oxidative stress, intense light exposure and oxygen imbalances such as hypoxic or hyperoxic conditions perturb mitochondria, nuclear function and further lead to cellular damage of retina and retinal pigment epithelial (RPE) cells. Our major aim is to understand the various biochemical and proteomic events that occur during the progression of retina and RPE cell death. The comprehensive objectives of this dissertation are to understand the functional aspects of protein expression, posttranslational modifications, protein or lipid binding changes, phenotypic, morphological alterations and their regulation during the retina and RPE apoptosis under oxidative stress. The entire study is divided into four chapters …

Cerium Oxide Nanoparticles Sensitize Pancreatic Cancer Cells To Radiation By Promoting Acidic Ph, Ros, And Jnk Dependent Apoptosis, Melissa Wason

Electronic Theses and Dissertations

Side effects of radiation therapy (RT) remain the most challenging issue for pancreatic cancer treatment. In this report we determined whether and how cerium oxide nanoparticles (CONPs) sensitize pancreatic cancer cells to RT. CONP pretreatment enhanced radiation-induced reactive oxygen species (ROS) production preferentially in acidic cell-free solutions as well as acidic human pancreatic cancer cells. In acidic environments, CONPs favor the scavenging of superoxide radical over the hydroxyl peroxide resulting in accumulation of the latter whereas in neutral pH CONPs scavenge both. CONP treatment prior to RT markedly potentiated the cancer cell apoptosis both in culture and in tumors and …

The Role Of Mitochondrial Omi/Htra2 Protease In Protein Quality Control And Mitophagy, Camilla Ambivero

Electronic Theses and Dissertations

Omi/HtrA2 is a mitochondrial serine protease with a dual and opposite function depending on its subcellular localization. Most of the previous studies focused on Omi/HtrA2’s pro-apoptotic function when the protein is released to the cytoplasm. It is becoming apparent that the main function of Omi/HtrA2 is within the mitochondria, where it has a pro-survival role. However, its mechanism is still poorly understood. To this end, we used the yeast two-hybrid system to dissect the Omi/HtrA2 pathway by identifying novel interactors and substrates. Our studies revealed a novel function of Omi/HtrA2 in the regulation of a deubiquitinating (DUB) complex. In addition …

The Time-Course Of The Effects Of Growth Hormone During Zebrafish (Danio Rerio) Auditory Hair Cell Regeneration, Yajie Wang

Masters Theses & Specialist Projects

Growth hormone (GH) was upregulated in the zebrafish inner ear following sound exposure in a previous study. To identify the specific role of GH in hair cell regeneration and the possible cellular mechanisms of this regeneration, groups of zebrafish were divided into baseline (no sound exposure, no injection), buffer-injected and GH-injected groups. Buffer- and GH-injected fish were exposed to a 150 Hz tone at a source level of 179 dB re 1 μPa root mean squared (RMS) for 36 h. Phalloidin-staining was used to assess the effects of GH on hair cell bundle density; BrdU-labeling was used to assess the …

Prostate Cancer-Specific And Potent Antitumor Effect Of A Dd3-Controlled Oncolytic Virus Harboring The Pten Gene, Miao Ding, Xin Cao, Hai-Neng Xu, Jun-Kai Fan, Hong-Ling Huang, Dong-Qin Yang, Yu-Hua Li, Jian Wang, Runsheng Li, Xin-Yuan Liu

Molecular and Cellular Biochemistry Faculty Publications

Prostate cancer is a major health problem for men in Western societies. Here we report a Prostate Cancer-Specific Targeting Gene-Viro-Therapy (CTGVT-PCa), in which PTEN was inserted into a DD3-controlled oncolytic viral vector (OV) to form Ad.DD3.E1A.E1B(Δ55)-(PTEN) or, briefly, Ad.DD3.D55-PTEN. The woodchuck post-transcriptional element (WPRE) was also introduced at the downstream of the E1A coding sequence, resulting in much higher expression of the E1A gene. DD3 is one of the most prostate cancer-specific genes and has been used as a clinical bio-diagnostic marker. PTEN is frequently inactivated in primary prostate cancers, which is crucial for prostate cancer progression. Therefore, the Ad.DD3.D55-PTEN …

Transplantation Of Pluripotent Stem Cells Confers Cardiac Protection In Dox-Induced Heart Failure Through Notch-1 Pathway, Hilda Merino-Chavez

Electronic Theses and Dissertations

Doxorubicin (DOX) is the antineoplastic drug of preference used to treat a wide variety of malignancies, with high survival rates among treated patients. However, the benefits of this drug have become less appealing due to the side effects that occur such as DOX-induced cardiomyopathy (DIC) and an increased risk of myocardial infarction (MI). Therefore, there is an urgent need to explore the therapeutic options to treat DIC. In this context, adult stem cells have been used as a source to reduce cardiomyocyte apoptosis in DIC; however, the effects of transplanted embryonic stem (ES) cells and induced pluripotent stem (iPS) cells …

Consumption Of High Ω-3 Fatty Acid Diet Suppressed Prostate Tumorigenesis In C3(1) Tag Mice, Juliana A. Akinsete, Gabriela Ion, Theodore R. Witte, W. Elaine Hardman

Biochemistry and Microbiology

Prostate cancer incidence and mortality are high in the Western world and high ω-6/ω-3 PUFA in the Western diet may be a contributing factor. We investigated whether changing from a diet that approximates ω-6 fat content of the Western diet to a high ω-3 fat diet at adulthood might reduce prostate cancer risk. Female SV 129 mice that had consumed a high ω-6 diet containing corn oil for 2 weeks were bred with homozygous C3(1)Tag transgenic male mice. All male offspring were weaned to the corn oil diet (CO) until postpuberty when half of the male offspring were transferred to …

The Dynamic Functions Of Bax Are Dependent On Key Structural And Regulatory Features, Rebecca Boohaker

Electronic Theses and Dissertations

Bax is an essential mediator of cell fate. Since its discovery in 1985 as a protein that interacts with the anti-apoptotic protein, Bcl-2, key elements related to its function, structure and regulation remains to be determined. To this end, mitochondrial metabolism was examined in non-apoptotic Bax-deficient HCT-116 cells as well as primary hepatocytes from Bax-deficient mice. Although mitochondrial density and mitochondrial DNA content was the same in Bax-containing and Bax -deficient cells, MitoTracker staining patterns differed, suggesting the existence of Bax -dependent functional differences in mitochondrial physiology. Oxygen consumption and cellular ATP levels were reduced in Bax -deficient cells, while …

Discovery Of Marinopyrrole A (Maritoclax) As A Selective Mcl-1 Antagonist That Overcomes Abt-737 Resistance By Binding To And Targeting Mcl-1 For Proteasomal Degradation*, Kenichiro Doi, Rongshi Li, Shen-Shu Sung, Hongwei Wu, Yan Liu, Wanda Manieri, Gowdahalli Krishnegowda, Andy Awwad, Alden Dewey, Xin Liu, Shantu Amin, Chunwei Cheng, Yong Qin, Ernst Schonbrunn, Gary W. Daughdrill, Thomas P. Loughran Jr., Said M. Sebti, Hong-Gang Wang

Molecular Biosciences Faculty Publications

The anti-apoptotic Bcl-2 family of proteins, including Bcl-2, Bcl-XL and Mcl-1, are well-validated drug targets for cancer treatment. Several small molecules have been designed to interfere with Bcl-2 and its fellow pro-survival family members. While ABT-737 and its orally active analog ABT-263 are the most potent and specific inhibitors to date that bind Bcl-2 and Bcl-XL with high affinity but have a much lower affinity for Mcl-1, they are not very effective as single agents in certain cancer types because of elevated levels of Mcl-1. Accordingly, compounds that specifically target Mcl-1 may overcome this resistance. In this study, we identified …

Signals Delivered By Interleukin-7 Regulate The Activities Of Bim And Jund In T Lymphocytes, Shannon Moore Ruppert

Electronic Theses and Dissertations

Interleukin-7 (IL-7) is an essential cytokine for lymphocyte growth that has the potential for promoting proliferation and survival. While the survival and proliferative functions of IL-7 are well established, the identities of IL-7 signaling components in pathways other than JAK/STAT, that accomplish these tasks remain poorly defined. To this end, we used IL-7 dependent T-cells to examine those components necessary for cell growth and survival. Our studies revealed two novel signal transducers of the IL-7 growth signal: BimL and JunD. IL-7 promoted the activity of JNK (Jun N-terminal Kinase), and that JNK, in turn, drove the expression of JunD, a …

Hdm2 Small-Molecule Inhibitors For Therapeutic Intervention In B-Cell Lymphoma, Angela Sosin

Wayne State University Dissertations

Lymphomas frequently retain wild-type (wt) p53 function but overexpress HDM2, compromising p53 activity. Therefore, lymphoma is a suitable model for studying therapeutic value of disrupting HDM2-p53 association by small-molecule inhibitors (SMIs). HDM2 SMIs have been developed and are currently under various stages of preclinical and clinical investigation. This study examined various molecular mechanisms associated and biological effects of two different classes of HDM2 SMIs: the spiro-oxindoles (MI-219) and cis-imidazoline (Nutlin-3) in lymphoma cell lines and patient-derived B-lymphoma cells. Surprisingly, results revealed significant quantitative and qualitative differences between these two agents. At the molecular level, effect of Nutlin-3 was generally more …

Stomatin-Like Protein 2 Binds Cardiolipin And Regulates Mitochondrial Biogenesis And Function., Darah Christie, Caitlin D Lemke, Isaac M Elias, Luan A Chau, Mark G Kirchhof, Bo Li, Eric H Ball, Stanley D Dunn, Grant M Hatch, Joaquín Madrenas

Biochemistry Publications

Stomatin-like protein 2 (SLP-2) is a widely expressed mitochondrial inner membrane protein of unknown function. Here we show that human SLP-2 interacts with prohibitin-1 and -2 and binds to the mitochondrial membrane phospholipid cardiolipin. Upregulation of SLP-2 expression increases cardiolipin content and the formation of metabolically active mitochondrial membranes and induces mitochondrial biogenesis. In human T lymphocytes, these events correlate with increased complex I and II activities, increased intracellular ATP stores, and increased resistance to apoptosis through the intrinsic pathway, ultimately enhancing cellular responses. We propose that the function of SLP-2 is to recruit prohibitins to cardiolipin to form cardiolipin-enriched …

Discovery Of An Apoptosis Inducing Ligand For Burkitt Lymphoma, Carolyn Laymon, Kyla Bradylong, Mary Saunders, David Olivos, Kit Lam

STAR Program Research Presentations

One-bead two-compound (OB2C) combinatorial chemistry libraries enable the discovery of novel synthetic compounds which can be used to evoke specific signaling response in cells. The library configuration is composed of a fixed known cell adhesion ligand and a random chemical library displayed on the surface of Tentagel beads. The cell adhesion ligand binds to specific receptors located on the surface of cells enabling the random immobilized chemical molecules on each bead resin bead to evoke specific cellular responses such as apoptosis or cell death. To validate this concept, a OB2C combinatorial library comprised of an α4β1 integrin targeting ligand, LLP2A, …

Echogenic Liposomes For Nitric Oxide Delivery And Breast Cancer Treatment, Soo Yeon Lee Female

Dissertations and Theses (Open Access)

Liposomes, also known as nontoxic, biodegradable, and non-immunogenic therapeutic delivery vehicles, have been proposed as a carrier for drugs and antitumor agents in cancer chemotherapy. Echogenic liposomes (ELIP) have the potential to entrap air or bioactive gas to enhance acoustic reflectivity in ultrasound and are used as a contrast agent. The innovative part of this study is based on a novel concept to encapsulate nitric oxide (NO) gas into ELIP, deliver it to breast cancer cells, and control its release via direct ultrasound exposure. Studies on the effect of NO in tumor biology have shown that a high levels of …

Downregulation Of Pax2 Suppresses Ovarian Cancer Cell Growth, Huijuan Song

Dissertations and Theses (Open Access)

PAX2 is one of nine PAX genes regulating tissue development and cellular differentiation in embryos. PAX2 promotes cell proliferation, oncogenic transformation, cell-lineage specification, migration, and survival. Unattenuated PAX2 has been found in several cancer types. We therefore sought to elucidate the role of PAX2 in ovarian carcinomas. We found that PAX2 was expressed in low-grade serous, clear cell, endometrioid and mucinous cell ovarian carcinomas, which are relatively chemoresistant compared to high grade serous ovarian carcinomas. Four ovarian cancer cell lines, RMUGL (mucinous), TOV21G (clear cell), MDAH-2774 (endometrioid) and IGROV1 (endometrioid), which express high-levels of PAX2, were used to study the …

Changes In Expression Of Akt Pathway Proteins Following Treatment With Rg3 In Vitro, Kathryn Schalkoff

All Theses

To assess changes in AKT pathway signaling, a recombinant protein of the G3 domain of rat laminin-5 (rG3) that specifically binds the alpha subunit of integrins α6β1 and α6β4 expressed on cancer cells (e.g., MDA-MB-231) was produced. This recombinant protein is believed to interrupt the intracellular signaling events of the AKT pathway, causing a decrease in proliferation and survival of cells after treatment. Viability assays confirmed an apoptotic effect of rG3 on cells in a dose-dependent manner. However, data from gene expression studies of Caspase-9, GRB10, and CDKNIB proved non-conclusive that rG3 is acting upon gene expression, leading to the …

Nanosecond Pulsed Electric Field Induction Of Programmed Cell Death Is Cell Type Dependent: An In Vitro Study, Wei Ren

Theses and Dissertations in Biomedical Sciences

Nanosecond pulsed electric fields (nsPEFs) present a novel and effective method for cancer ablation by eradicating the ubiquitous cancer hallmark of apoptosis evasion and enforcing cancer programmed cell death. To develop nsPEFs as an anticancer method, a comprehensive understanding of cell death mechanisms is required. The overall objective of this dissertation is to elucidate molecular mechanisms underlying effects of nsPEFs on E4 murine squamous cell carcinoma and human T-cell Jurkat clones that are wildtype, deficient in FADD (ΔFADD) and deficient in caspase-8 (ACas-8). The overall hypothesis is that nsPEFs eliminate cancer cells through activating caspase-dependent and caspase-independent programmed cell death …

Effects Of Canola And Corn Oil Mimetic On Jurkat Cells, Gabriela Ion, Kayla Fazio, Juliana A. Akinsete, W. Elaine Hardman

Biochemistry and Microbiology

BACKGROUND: The Western diet is high in omega-6 fatty acids and low in omega-3 fatty acids. Canola oil contains a healthier omega 3 to omega 6 ratio than corn oil. Jurkat T leukemia cells were treated with free fatty acids mixtures in ratios mimicking that found in commercially available canola oil (7% α-linolenic, 30% linoleic, 54% oleic) or corn oil (59% linoleic, 24% oleic) to determine the cell survival or cell death and changes in expression levels of inflammatory cytokines and receptors following oil treatment.

METHODS: Fatty acid uptake was assessed by gas chromatography. Cell survival and cell death were …

Infection With Chlamydia Pneumoniae In Neuronal Cells Alters The Expression Of Genes Involved In Apoptosis And Autophagy Pathways, Annette K. Slutter

PCOM Biomedical Studies Student Scholarship

Dysfunctions in cellular mechanisms such as apoptosis and autophagy have been implicated in the neurodegeneration associated with Alzheimer’s disease (AD). Autophagy in AD pathogenesis has been linked to the endosomal-lysosomal system, which has been shown to play a role in amyloid processing. Studies have suggested that apoptosis may contribute to the neuronal cell loss observed in AD; however, there is no evidence of the apoptotic process leading to terminal completion. Aβ1-42 has been shown to induce apoptosis in neurons and may be an initiating factor in AD. Our previous studies demonstrated that neurons infected with C. pneumoniae are resistant to …

Release Of Hmgb1 In Response To Pro-Apoptotic Glioma Killing Strategies: Efficacy And Neurotoxicity, Marianela Candolfi, Kader Yagiz, David Foulad, Gabrielle Alzadeh, Matthew Tesarfreund, Akm Ghulam Muhammad, Mariana Puntel, Kurt Kroeger, Chunyan Liu, Sharon Lee, James Curtin, Gwendalyn D. King, Jonathan Lerner, Katsuaki Sato, Yohei Mineharu, Weidong Xiong, Pedro R. Lowenstein, Maria Castro

Articles

Purpose In preparation for a Phase I clinical trial utilizing a combined cytotoxic/immunotherapeutic strategy using adenoviruses expressing Flt3L (Ad-Flt3L) and thymidine kinase (Ad-TK) to treat glioblastoma (GBM), we tested the hypothesis that Ad-TK+GCV would be the optimal tumor killing agent in relation to efficacy and safety when compared to other pro-apoptotic approaches. Experimental Design and Results The efficacy and neurotoxicity of Ad-TK+GCV was compared with Ads encoding the pro-apoptotic cytokines (TNF-α, TRAIL, FasL), alone or in combination with Ad-Flt3L. In rats bearing small GBMs (day 4), only Ad-TK+GCV or Ad-FasL improved survival. In rats bearing large GBMs (day 9), the …

Studies On Inositol Polyphosphates And Their Role In Programmed Cell Death, Rakhee Agarwal

Theses and Dissertations

The agents that induce apoptosis in cancerous cells are considered as potential candidates for cancer therapy. Inositol polyphosphates, the naturally occurring compounds, regulate diverse cellular processes including induction of apoptosis in certain cancerous cells and hence can be considered as potential anticancer agents. The aim of this research dissertation was to establish firmly the role of inositol polyphosphates in induction of apoptosis by examining their mechanism of action. The overall hypothesis was that alterations in intracellular levels of inositol polyphosphates would bring about apoptotic changes. The hypothesis was tested by changing endogenous inositol polyphosphates by way of chemical treatments known …

Nanosecond Pulsed Electric Fields Induce A Mitochondria-Independent Apoptosis In B16f10 Melanoma Cells In Vitro, Wentia Elissa Ford

Theses and Dissertations in Biomedical Sciences

Nanosecond pulsed electric fields (nsPEFs) are ultra-short pulses that induce direct electric field and biological effects that initiate apoptosis. Here the application of ten 300ns pulses ranging in electric fields from 12kV/cm-60kV/cm was administered to determine the effects on B16F10 melanoma cells evaluated by in vitro studies. Initial application of nsPEFs demonstrated apoptosis induction in an electric field- and pulse number-dependent manner measured by caspase activation that correlated with decrease in cell viability 24hr post pulse. In addition caspase activity was shown to be independent of calcium mobilization though ions may play a part in other aspects of apoptosis. The …

Retinoic Acid Decreases Atf-2 Phosphorylation And Sensitizes Melanoma Cells To Taxol-Mediated Growth Inhibition, Ying Huang, Jennifer Minigh, Sarah Miles, Richard N. Niles

Biochemistry and Microbiology

Cutaneous melanoma is often resistant to chemo- and radiotherapy. This resistance has recently been demonstrated to be due, at least in part, to high activating transcription factor 2 (ATF-2) activity in these tumors. In concordance with these reports, we found that B16 mouse melanoma cells had higher levels of ATF-2 than immortalized, but non-malignant mouse melanocytes. In addition, the melanoma cells had a much higher amount of phosphorylated (active) ATF-2 than the immortalized melanocytes. In the course of determining how retinoic acid (RA) stimulates activating protein-1 (AP-1) activity in B16 melanoma, we discovered that this retinoid decreased the phosphorylation of …

Nanosecond Pulsed Electric Field Effects On Cell Cycle And Apoptosis, Emily H. Hall

Theses and Dissertations in Biomedical Sciences

Apoptosis, programmed cell death, is a highly regulated and complex pathway essential for embryonic development, immune-system function and maintenance of tissue homeostasis where cells induce their own cell death. Cells undergoing apoptosis exhibit a distinctive phenotype characterized by maintenance of membrane integrity, cell shrinkage, phosphatidylserine (PS) externalization at the plasma membrane, caspase protease activation, DNA fragmentation, release of cytochrome c from the mitochondrion, and membrane blebbing. An important regulatory protein in the apoptotic pathway is p53. The p53 protein functions to modulate the cell cycle by arresting cells in the G1 and G 2 phases to repair DNA damage, and/or …