Different functional domains of the adenovirus E1A gene are involved in regulation of host cell cycle products.

Zerler, Brad; Roberts, Richard J.; Mathews, Michael B.; Morán, Elizabeth

doi:10.1128/mcb.7.2.821

Cited by 176 publications

(145 citation statements)

References 77 publications

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“…We conclude that the 12S ElA gene product does possess transcription-inducing activity but that the efficiency of this activity depends on the target gene. The hsp7O gene may not be the only example of ElA-12S-mediated stimulation since it was recently shown that there is an increase in synthesis of the proliferating cell nuclear antigen in either 12S or 13S virus infection of primary baby rat kidney cells (59). Of potential interest is the fact that these two genes induced by the 12S ElA mutant (if indeed proliferating cell nuclear antigen gene induction is transcriptional) are also induced by an addition of serum to starved cultures.…”

Section: Simon Et Al In Preparation)mentioning

confidence: 99%

Selective induction of human heat shock gene transcription by the adenovirus E1A gene products, including the 12S E1A product.

Simon¹,

Kitchener²,

Kao³

et al. 1987

Mol. Cell. Biol.

111

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We have previously shown that the human 70-kilodalton heat shock protein gene (hsp7O) is induced by the adenovirus ElA gene product and during the S-G2 phase of the cell cycle. In this study, we investigated the effect of ElA on the expression of other human hsp genes. A gene encoding one form of the hsp89 protein (hsp89a) was activated during an adenovirus infection with kinetics similar to those of activation of hsp7O. The induction required a functional ElA gene. However, the hsp89 transcript was not cell cycle regulated. Genes encoding another form of hsp89 and the hsp27 protein were not induced by ElA or during the cell cycle. Further examination of hsp7O expression revealed a greater complexity than previously seen. Si nuclease analysis using an hsp70 cDNA as well as a distinct hsp7O genomic clone demonstrated three related hsp70 transcripts; two were induced by ElA, and one was not. Both of the ElA-inducible genes were regulated during the cell cycle. All three were induced by heat shock. These results suggest common aspects of control among certain members of this family of cellular genes distinct from heat shock control. Finally, using viruses that express the individual ElA proteins, we found that the hsp70 gene is induced by the 12S and the 13S ElA products. The efficiency of induction by the 12S product was somewhat less than that by the 13S product but only by a factor of less than 2. This is in contrast to the induction of early viral genes, for which the 13S product is considerably more efficient than the 12S product.

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Section: Simon Et Al In Preparation)mentioning

confidence: 99%

Selective induction of human heat shock gene transcription by the adenovirus E1A gene products, including the 12S E1A product.

Simon¹,

Kitchener²,

Kao³

et al. 1987

Mol. Cell. Biol.

111

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“…The human papillomavirus E6 oncoprotein, which targets p53 for degradation, was found to attenuate mitotic delay in normal human ®broblasts only after an extended period of cell replication . Adenovirus E1A, another DNA tumor virus oncoprotein, can drive quiescent cells into both DNA replication and mitosis (Zerler et al, 1987). The domains of E1A required for these two functions are separable, implying that E1A interacts with cellular proteins that regulate entry into mitosis and that these proteins are distinct from those regulating entry into S phase.…”

Section: Introductionmentioning

confidence: 99%

Disregulation of mitotic checkpoints and regulatory proteins following acute expression of SV40 large T antigen in diploid human cells

Chang

Ray

et al. 1997

Oncogene

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SV40 large T antigen (T) inactivates the tumor suppressor proteins p53 and pRb, and can induce cells to enter DNA replication at inappropriate times. We show here that T also compromises three cell cycle checkpoints that regulate the entry into and exit from mitosis. Human diploid ®broblasts infected with a retrovirus expressing T displayed an attenuated radiation-induced mitotic delay, were more susceptible to chemical-induced uncoupling of mitosis from the completion of DNA replication, and were more likely to exit mitosis and rereplicate their DNA when mitotic spindle assembly was inhibited. Consistent with altered mitotic checkpoint control, cells expressing T displayed elevated protein levels and/or associated activities of the mitotic regulatory proteins cyclin A, cyclin B, Cdc25C and p34 cdc2 . These changes in mitotic control were evident within 5 ± 10 population doublings after retroviral infection, indicating a direct e ect of T expression. Cells acutely infected with the T-expressing retrovirus su ered numerical and structural chromosome aberrations, including increases in aneuploidy, dicentric chromosomes, chromatid exchanges and chromosome breaks and gaps. These ®ndings indicate that T rapidly disrupts mitotic checkpoints that help maintain genomic stability, and suggest mechanisms by which T induces chromosome aberrations and promotes the immortalization and neoplastic transformation of human cells.

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“…The E1A CR2 domain is known to bind with the RB family of proteins, leading to immortalization of the primary culture cells and in cooperation with ras or E1B oncogenes, E1A can lead to transformation (Whyte et al, 1989;Corbeil and Branton, 1994). Deletion of the CR2 domain or even a site mutation to knock out the RB-binding site on E1A is su cient to abolish the immortalization function of E1A (Lillie et al, 1986;Moran et al, 1986;Zerler et al, , 1987Schneider et al, 1987;Kuppuswamy and Chinnadurai, 1987;Smith and Zi , 1988;Jelsma et al, 1989;Whyte et al, 1989). Thus, the deletion of the CR2 and CR3 domains in the mini-E1A would abolish the potential risk of immortalization and consequent transformation caused by wild type E1A.…”

Section: Discussionmentioning

confidence: 99%

Mapping of adenovirus 5 E1A domains responsible for suppression of neu-mediated transformation via transcriptional repression of neu

Chen

Chinnadurai

et al. 1997

Oncogene

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Overexpression of neu (also known as c-erbB-2 or HER-2) commonly occurs in human cancer and is also known to enchance tumor metastasis and chemoresistance. Our earlier reports showed that the adenovirus 5 E1A can suppresss the neu-mediated transformation by repression of neu. Thus, E1A has the potential to be used as a therapeutic agent against the neu-overexpressing human cancers. However, a serious concern to this approach is that E1A is also capable of immortalizing primary culture cells and can co-operate with ras or E1B oncogenes to transform them. The E1A CR2 domain (amino acid residues 120 to 140) necessary for binding to RB is believed to be required for this oncogenic function. Here, we report that deletion of CR2 region did not a ect E1A's capability to repress neu. Interestingly, deletion of the amino acid residues 4 to 25 or 40 to 80 completely disrupted E1A-mediated neu repression. By deleting the amino acid residues from 81 to 185, we have successfully generated a mini-E1A mutant that was su cient to inhibit neu promoter activity and suppress neu-mediated transformation. The mini-E1A mutant does not contain the CR2 domain that is crucial for RB binding and immortalization, and hence, may serve as a more selective tumor suppressor, and a safer therapeutic agent. It may also be a useful tool to further investigate the molecular mechanism(s) of neu overexpression and E1A-mediated transcriptional repression in cancer cells.

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Different functional domains of the adenovirus E1A gene are involved in regulation of host cell cycle products.

Cited by 176 publications

References 77 publications

Selective induction of human heat shock gene transcription by the adenovirus E1A gene products, including the 12S E1A product.

Selective induction of human heat shock gene transcription by the adenovirus E1A gene products, including the 12S E1A product.

Disregulation of mitotic checkpoints and regulatory proteins following acute expression of SV40 large T antigen in diploid human cells

Mapping of adenovirus 5 E1A domains responsible for suppression of neu-mediated transformation via transcriptional repression of neu

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