scholarly journals Distinct cell death pathways triggered by the adenovirus early region 4 ORF 4 protein

2002 ◽  
Vol 158 (3) ◽  
pp. 519-528 ◽  
Author(s):  
Amélie Robert ◽  
Marie-Joëlle Miron ◽  
Claudia Champagne ◽  
Marie-Claude Gingras ◽  
Philip E. Branton ◽  
...  
Keyword(s):  
Cell Death ◽  
Critical Role ◽  
Adenovirus Type ◽  
Cell Types ◽  
Specific Cell ◽  
Nuclear Targeting ◽  
Early Region ◽  
Delayed Cell Death ◽  
Distinct Cell ◽  
Early Region 4

In transformed cells, induction of apoptosis by adenovirus type 2 (Ad2) early region 4 ORF 4 (E4orf4) correlates with accumulation of E4orf4 in the cell membrane–cytoskeleton fraction. However, E4orf4 is largely expressed in nuclear regions before the onset of apoptosis. To determine the relative contribution of nuclear E4orf4 versus membrane-associated E4orf4 to cell death signaling, we engineered green fluorescent fusion proteins to target E4orf4 to specific cell compartments. The targeting of Ad2 E4orf4 to cell membranes through a CAAX-box or a myristylation consensus signal sufficed to mimic the fast Src-dependent apoptotic program induced by wild-type E4orf4. In marked contrast, the nuclear targeting of E4orf4 abolished the early induction of extranuclear apoptosis. However, nuclear E4orf4 still induced a delayed cell death response independent of Src-like activity and of E4orf4 tyrosine phosphorylation. The zVAD.fmk-inhibitable caspases were dispensable for execution of both cell death programs. Nevertheless, both pathways led to caspase activation in some cell types through the mitochondrial pathway. Finally, our data support a critical role for calpains upstream in the death effector pathway triggered by the Src-mediated cytoplasmic death signal. We conclude that Ad2 E4orf4 induces two distinct cell death responses, whose relative contributions to cell killing may be determined by the genetic background.

scholarly journals The Early Region 4 orf4 Protein of Human Adenovirus Type 5 Induces p53-Independent Cell Death by Apoptosis

1998 ◽  
Vol 72 (9) ◽  
pp. 7144-7153 ◽  
Author(s):  
Richard C. Marcellus ◽  
Josée N. Lavoie ◽  
Dominique Boivin ◽  
Gordon C. Shore ◽  
Gary Ketner ◽  
...  
Keyword(s):  
Cell Death ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Cell Killing ◽  
Wild Type Virus ◽  
Dna Encoding ◽  
Early Region ◽  
Orf4 Protein ◽  
Early Region 4 ◽  
Adenovirus Type 5

ABSTRACT Previous studies by our group showed that infection of human and rodent cells by human adenovirus type 5 (Ad5) results in the induction of p53-independent apoptosis and cell death that are dependent upon transactivation of early region 4 (E4). To identify which E4 products are involved, studies were conducted with p53-deficient human SAOS-2 cells infected with various Ad5 E4 mutants. An E4orf6-deficient mutant was defective in cell killing, whereas another that expressed only E4orf6 and E4orf4 killed like wild-type virus, suggesting that E4orf6 may be responsible for cytotoxicity; however, a mutant expressing only E4orf4 induced high levels of cell death, indicating that this E4 product may also be able to induce cytotoxicity. To define the E4 cell death-inducing functions more precisely, cDNAs encoding individual E4 products were introduced into cells by DNA transfection in the absence of other Ad5 proteins. In cotransfections with a cDNA encoding firefly luciferase, enzymatic activity was high in all cases except with E4orf4, where luciferase levels were less than 20% of those in controls. In addition, drug selection of several cell types following transfection with retroviral vector DNA encoding individual E4 products as well as puromycin resistance yielded a large number of cell colonies except when E4orf4 was expressed. These data demonstrated that E4orf4 is the only E4 product capable of independent cell killing. Cell death induced by E4orf4 was due to apoptosis, as evidenced by 4′,6-diamidino-2-phenylindole (DAPI) staining of cell nuclei in E4orf4-expressing cells. Thus, although E4orf6 may play some role, these results suggested that E4orf4 may be the major E4 product responsible for induction of p53-independent apoptosis.

scholarly journals Mutational Analysis of Early Region 4 of Bovine Adenovirus Type 3

Virology ◽  
2001 ◽  
Vol 290 (1) ◽  
pp. 153-163 ◽  
Author(s):  
Mohit K. Baxi ◽  
Jill Robertson ◽  
Lorne A. Babiuk ◽  
Suresh K. Tikoo
Keyword(s):  
Mutational Analysis ◽  
Adenovirus Type ◽  
Bovine Adenovirus ◽  
Early Region ◽  
Early Region 4 ◽  
Bovine Adenovirus Type 3 ◽  
Type 3

scholarly journals Cellular Functions of OCT-3/4 Regulated by Ubiquitination in Proliferating Cells

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 663
Author(s):  
Kwang-Hyun Baek ◽  
Jihye Choi ◽  
Chang-Zhu Pei
Keyword(s):  
Stem Cells ◽  
Cellular Proliferation ◽  
Critical Role ◽  
Embryonic Stem ◽  
Cell Types ◽  
Ubiquitin Proteasome System ◽  
Specific Cell ◽  
Cellular Mechanisms ◽  
Proliferating Cells ◽  
Proliferation And Differentiation

Octamer-binding transcription factor 3/4 (OCT-3/4), which is involved in the tumorigenesis of somatic cancers, has diverse functions during cancer development. Overexpression of OCT-3/4 has been detected in various human somatic tumors, indicating that OCT-3/4 activation may contribute to the development and progression of cancers. Stem cells can undergo self-renewal, pluripotency, and reprogramming with the help of at least four transcription factors, OCT-3/4, SRY box-containing gene 2 (SOX2), Krüppel-like factor 4 (KLF4), and c-MYC. Of these, OCT-3/4 plays a critical role in maintenance of undifferentiated state of embryonic stem cells (ESCs) and in production of induced pluripotent stem cells (iPSCs). Stem cells can undergo partitioning through mitosis and separate into specific cell types, three embryonic germ layers: the endoderm, the mesoderm, and the trophectoderm. It has been demonstrated that the stability of OCT-3/4 is mediated by the ubiquitin-proteasome system (UPS), which is one of the key cellular mechanisms for cellular homeostasis. The framework of the mechanism is simple, but the proteolytic machinery is complicated. Ubiquitination promotes protein degradation, and ubiquitination of OCT-3/4 leads to regulation of cellular proliferation and differentiation. Therefore, it is expected that OCT-3/4 may play a key role in proliferation and differentiation of proliferating cells.

scholarly journals Chemogenetic Tools for Causal Cellular and Neuronal Biology

2018 ◽  
Vol 98 (1) ◽  
pp. 391-418 ◽  
Author(s):  
Deniz Atasoy ◽  
Scott M. Sternson
Keyword(s):  
G Protein ◽  
Ex Vivo ◽  
Cell Types ◽  
Cell Populations ◽  
Specific Cell ◽  
Cellular Processes ◽  
Distinct Cell ◽  
G Protein Coupled ◽  
Pharmacological Control

Chemogenetic technologies enable selective pharmacological control of specific cell populations. An increasing number of approaches have been developed that modulate different signaling pathways. Selective pharmacological control over G protein-coupled receptor signaling, ion channel conductances, protein association, protein stability, and small molecule targeting allows modulation of cellular processes in distinct cell types. Here, we review these chemogenetic technologies and instances of their applications in complex tissues in vivo and ex vivo.

scholarly journals Activation of Adenovirus Type 2 Early Region 4 ORF4 Cytoplasmic Death Function by Direct Binding to Src Kinase Domain

2004 ◽  
Vol 279 (24) ◽  
pp. 25905-25915 ◽  
Author(s):  
Claudia Champagne ◽  
Marie-Claude Landry ◽  
Marie-Claude Gingras ◽  
Josée N. Lavoie
Keyword(s):  
Src Kinase ◽  
Adenovirus Type ◽  
Kinase Domain ◽  
Early Region ◽  
Direct Binding ◽  
Early Region 4 ◽  
Adenovirus Type 2

scholarly journals STING Signaling Promotes Apoptosis, Necrosis, and Cell Death: An Overview and Update

2018 ◽  
Vol 2018 ◽  
pp. 1-4 ◽  
Author(s):  
Song Liu ◽  
Wenxian Guan
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Tumor Immunity ◽  
Host Defense ◽  
Cell Types ◽  
Immune Homeostasis ◽  
Induce Cell Death ◽  
Distinct Cell ◽  
Clinical Strategies ◽  
Apoptosis And Necrosis

STING is a newly identified intracellular sensor of foreign and endogenous DNA. STING has been recognized as an activator of immune responses by TBK1/IRF3 and NF-κB pathways, and it is suggested to play critical roles in host defense, autoimmune diseases, and tumor immunity. Recent studies have revealed that the outcome of STING activation could vary between distinct cell types and scenarios. STING activation in certain cell types triggered cell death including apoptosis and necrosis. This effect could be critical for preventing unnecessary or excessive inflammatory events and maintaining host immune homeostasis. This review is dedicated to summarize recent evidences in the field of STING-mediated cell death and to demonstrate dual outcomes of STING signaling. Besides canonical immune responses represented by IFN and TNF productions, STING signaling can also induce cell death events in a variety of cell types. The double-faced characteristics of STING signaling requires further exploration and precious regulation before tailoring clinical strategies for associated diseases.

Early region 4 sequence and biological comparison of two isolates of mouse adenovirus type 1

Virology ◽  
1991 ◽  
Vol 180 (1) ◽  
pp. 257-265 ◽  
Author(s):  
Amy Oberhauser Ball ◽  
Clayton W. Beard ◽  
Pedro Villegas ◽  
Katherine R. Spindler
Keyword(s):  
Adenovirus Type ◽  
Early Region ◽  
Early Region 4

scholarly journals High Resolution Single Cell Maps Reveals Distinct Cell Organization and Function Across Different Regions of the Human Intestine

2021 ◽  
Author(s):  
John W Hickey ◽  
Winston R Becker ◽  
Stephanie A Nevins ◽  
Aaron M Horning ◽  
Almudena Espin Perez ◽  
...  
Keyword(s):  
Single Cell ◽  
Immune Surveillance ◽  
Cell Types ◽  
Open Chromatin ◽  
Specific Cell ◽  
Symbiotic Relationships ◽  
Distinct Cell ◽  
Cell Organization ◽  
Reference Map ◽  
And Function

The colon is a complex organ that promotes digestion, extracts nutrients, participates in immune surveillance, maintains critical symbiotic relationships with microbiota, and affects overall health. To better understand its organization, functions, and its regulation at a single cell level, we performed CODEX multiplexed imaging, as well as single nuclear RNA and open chromatin assays across eight different intestinal sites of four donors. Through systematic analyses we find cell compositions differ dramatically across regions of the intestine, demonstrate the complexity of epithelial subtypes, and find that the same cell types are organized into distinct neighborhoods and communities highlighting distinct immunological niches present in the intestine. We also map gene regulatory differences in these cells suggestive of a regulatory differentiation cascade, and associate intestinal disease heritability with specific cell types. These results describe the complexity of the cell composition, regulation, and organization for this organ, and serve as an important reference map for understanding human biology and disease.

scholarly journals Analysis of Synthesis, Stability, Phosphorylation, and Interacting Polypeptides of the 34-Kilodalton Product of Open Reading Frame 6 of the Early Region 4 Protein of Human Adenovirus Type 5

1999 ◽  
Vol 73 (2) ◽  
pp. 1245-1253 ◽  
Author(s):  
Dominique Boivin ◽  
Megan R. Morrison ◽  
Richard C. Marcellus ◽  
Emmanuelle Querido ◽  
Philip E. Branton
Keyword(s):  
Protein Synthesis ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Open Reading Frame ◽  
Cellular Proteins ◽  
Cell Protein ◽  
Reading Frame ◽  
Early Region ◽  
Early Region 4 ◽  
Adenovirus Type 5

ABSTRACT The 34-kDa early-region 4 open reading frame 6 (E4orf6) product of human adenovirus type 5 forms complexes with both the cellular tumor suppressor p53 and the viral E1B 55-kDa protein (E1B-55kDa). E4orf6 can inhibit p53 transactivation activity, as can E1B-55kDa, and in combination these viral proteins cause the rapid turnover of p53. In addition, E4orf6-55kDa complexes play a critical role at later times in the regulation of viral mRNA transport and shutoff of host cell protein synthesis. In the present study, we have further characterized some of the biological properties of E4orf6. Analysis of extracts from infected cells by Western blotting indicated that E4orf6, like E1A and E1B products, is present at high levels until very late times, suggesting that it is available to act throughout the infectious cycle. This pattern is similar to that of E4orf4 but differs markedly from that of another E4 product, E4orf6/7, which is present only transiently. Synthesis of E4orf6 is maximal at early stages but ceases completely with the onset of shutoff of host protein synthesis; however, it was found that unlike E4orf6/7, E4orf6 is very stable, thus allowing high levels to be maintained even at late times. E4orf6 was shown to be phosphorylated at low levels. Coimmunoprecipitation studies in cells lacking p53 indicated that E4orf6 interacts with a number of other proteins. Five of these were shown to be viral or virally induced proteins ranging in size from 102 to 27 kDa, including E1B-55kDa. One such species, of 72 kDa, was shown not to represent the E2 DNA-binding protein and thus remains to be identified. Another appeared to be the L4 100-kDa nonstructural adenovirus late product, but it appeared to be present nonspecifically and not as part of an E4orf6 complex. Apart from p53, three additional cellular proteins, of 84, 19, and 14 kDa were detected by using an adenovirus vector that expresses only E4orf6. The 19-kDa species and a 16-kDa cellular protein were also shown to interact with E4orf6/7. It is possible that complex formation with these viral and cellular proteins plays a role in one or more of the biological activities associated with E4orf6 and E4orf6/7.

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