Functions of the two adenovirus early E1A proteins and their conserved domains in cell cycle alteration, actin reorganization, and gene activation in rat cells

Bellett, A. J. D.; Jackson, Paul; David, E T; Bennett, Eric J.; Cronin, Barbara

doi:10.1128/jvi.63.1.303-310.1989

Cited by 22 publications

(8 citation statements)

References 46 publications

(88 reference statements)

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“…Given the reliance on actin filaments for YAP activation in E1AKD293 cells, we propose that E1A inactivates YAP/TAZ indirectly by repressing genes required for assembly of the actin cytoskeleton. Previous work has reported that E1A disrupts the actin cytoskeleton (Bellett et al 1989;Fischer and Quinlan 2000). We found that actin genes (ACTA1, ACTA2, ACTG1, ACTB, and ACTBL2) and CDC42EP3 and CDC42EP5, which stimulate actin filament assembly, are all repressed by E1A.…”

Section: Indirect Regulation Of Yap/taz Nuclear Import By E1amentioning

confidence: 51%

Dedifferentiation by adenovirus E1A due to inactivation of Hippo pathway effectors YAP and TAZ

2019

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Adenovirus transformed cells have a dedifferentiated phenotype. Eliminating E1A in transformed human embryonic kidney cells derepressed ∼2600 genes, generating a gene expression profile closely resembling mesenchymal stem cells (MSCs). This was associated with a dramatic change in cell morphology from one with scant cytoplasm and a globular nucleus to one with increased cytoplasm, extensive actin stress fibers, and actomyosin-dependent flattening against the substratum. E1A-induced hypoacetylation at histone H3 Lys27 and Lys18 (H3K27/18) was reversed. Most of the increase in H3K27/18ac was in enhancers near TEAD transcription factors bound by Hippo signaling-regulated coactivators YAP and TAZ. E1A causes YAP/TAZ cytoplasmic sequestration. After eliminating E1A, YAP/TAZ were transported into nuclei, where they associated with poised enhancers with DNA-bound TEAD4 and H3K4me1. This activation of YAP/TAZ required RHO family GTPase signaling and caused histone acetylation by p300/CBP, chromatin remodeling, and cohesin loading to establish MSC-associated enhancers and then superenhancers. Consistent results were also observed in primary rat embryo kidney cells, human fibroblasts, and human respiratory tract epithelial cells. These results together with earlier studies suggest that YAP/TAZ function in a developmental checkpoint controlled by signaling from the actin cytoskeleton that prevents differentiation of a progenitor cell until it is in the correct cellular and tissue environment.

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Section: Indirect Regulation Of Yap/taz Nuclear Import By E1amentioning

confidence: 51%

Dedifferentiation by adenovirus E1A due to inactivation of Hippo pathway effectors YAP and TAZ

2019

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“…Others have, however, reported that region 1 is more important than region 2 for repression (61) and that only region 1 is required for the latter function (80). Thus, there is some disagreement regarding the assignment of functions to conserved regions, and, in fact, more recent reports cast further doubt on the hypothesis that separate domains of the ElA proteins specify individual ElA functions (3,72).…”

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confidence: 99%

Differential requirement for adenovirus type 12 E1A gene products in oncogenic transformation

Lamberti

Williams

1990

J Virol

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During the early period of infection, adenovirus type 12 ElA gene is expressed as overlapping, spliced mRNAs of 12 and 13S, which encode in-frame proteins of 235 and 266 amino acid residues (235R and 266R), respectively. To define the functions of these related products in the infection of human cells and transformation of rodent cells, we created single T-to-C transitions at the second base of each mRNA intron which specifically prevent splicing of the respective mRNAs. Mutant pm712 expresses only the 13S mRNA and 266R protein, while pm713 expresses only the 12S mRNA and 235R protein. By using these mutants, we showed that only the larger product is required for growth in human cells, including growth-arrested W138 cells, that the capacity to activate other viral genes (in human cells, at least) lies primarily with that protein, and that the 266R product is not required for autoregulation of its own transcription. In the presence of the 266R protein the 235R product was not required for complete and efficient transformation of a variety of rodent cells or for direct induction of tumors in rats, whereas in its absence the smaller product was insufficient for transformation or tumor induction. Finally, we showed that transformants resulting from infection of rodent cells with pm712 possess a fully-transformed phenotype and are tumorigenic. Previous studies with group C adenoviruses led to the conclusion that both ElA products are required for complete transformation; we conclude that with oncogenic serotype 12, only the 266R product is required for this process.

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“…The cytoplasmic translocation of E4orf4 has been shown to be associated with changes in the filamentous actin cytoskeleton and stably accumulated to perinuclear vesicles and cortical sites forming membrane protrusions [132]. E1A proteins also disrupt actin stress fibres in the context of viral infection in transformed rat cells [133]. Similarly, NS1 notably causes cytoskeleton collapse which manifests in degradation of filamentous actin and vimentin structures [134].…”

Section: Cytoskeleton Remodellingmentioning

confidence: 99%

Cancer Treatment Goes Viral: Using Viral Proteins to Induce Tumour-Specific Cell Death

Wyatt

Müller

Tavassoli

2019

Cancers

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Cell death is a tightly regulated process which can be exploited in cancer treatment to drive the killing of the tumour. Several conventional cancer therapies including chemotherapeutic agents target pathways involved in cell death, yet they often fail due to the lack of selectivity they have for tumour cells over healthy cells. Over the past decade, research has demonstrated the existence of numerous proteins which have an intrinsic tumour-specific toxicity, several of which originate from viruses. These tumour-selective viral proteins, although from distinct backgrounds, have several similar and interesting properties. Though the mechanism(s) of action of these proteins are not fully understood, it is possible that they can manipulate several cell death modes in cancer exemplifying the intricate interplay between these pathways. This review will discuss our current knowledge on the topic and outstanding questions, as well as deliberate the potential for viral proteins to progress into the clinic as successful cancer therapeutics.

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Functions of the two adenovirus early E1A proteins and their conserved domains in cell cycle alteration, actin reorganization, and gene activation in rat cells

Cited by 22 publications

References 46 publications

Dedifferentiation by adenovirus E1A due to inactivation of Hippo pathway effectors YAP and TAZ

Dedifferentiation by adenovirus E1A due to inactivation of Hippo pathway effectors YAP and TAZ

Differential requirement for adenovirus type 12 E1A gene products in oncogenic transformation

Cancer Treatment Goes Viral: Using Viral Proteins to Induce Tumour-Specific Cell Death

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