The Induction of Cellular DNA Synthesis in Quiescent Cells

By contrast to the complete inhibition of cellular DNA synthesis that follows adenovirus infection of growing, permissive cells, stationary, confluent human cells infected by Ad2 or Adl2 display an induction of cellular DNA synthesis (see for example, Ledinko, 1967 Takahashi et ai, 1969 Yamashita and Shimojo, 1969). In this respect, adenoviruses resemble papovaviruses such as SV40 or polyomavirus (Minowada and Moore, 1963 Winocour et ai, 1965 Dulbecco et ai, 1965 Weil et ai, 1965). Interestingly, a similar response is invoked in rodent cells, regardless of whether they are partially permissive or completely nonpermissive for the growth of the particular serotype with which they have been infected. As rodent cells are those that become transformed by human adenoviruses (see Tooze, 1980), the phenomenon of induction of cellular DNA synthesis has been viewed 

The induction of cellular DNA synthesis that occurs in adenovirus-infected rodent cells, and their subsequent progression through the cell cycle, carTB distinguished from the response of the same 

The induction of arrested mammalian cells into the cell cycle has also been well characterized with respect to events that precede DNA synthesis itself. These include synthesis of RNA and the induction of synthesis of such enzymes as thymidine kinase and ornithine decarboxylase (see Baserga, 1976 Pardee et al., 1978, for reviews). Quiescent cells that have been infected by an adenovirus do not display the accumulation of RNA that is typical of serum-stimulated cells (Pochron et al., 1980), nor is synthesis of ornithine decarboxylase induced (Cheetham and Bellett, 1982). Both serum stimulation and adenovirus infection do induce synthesis of thymidine kinase (Kit et al., 1965 Takahashi et al., 1966 Ledinko, 1967 Zimmerman et al., 1970), but the effects of simultaneous treatment with a-methyl-or-nithine indicate that the pathways of induction are not the same this agent has little effect on induction of thymidine kinase by Ad5, but inhibits the response to serum (Cheetham and Bellett, 1982). It, therefore, seems fair to conclude from this brief survey of the properties of the process whereby adenoviruses induce cellular DNA synthesis 

It seems only reasonable to suppose that the ability of adenoviruses to induce cellular DNA synthesis and entry into the cell cycle in mammalian cells is of advantage to the virus replication cycle such a property could hardly have evolved for any other purpose. Bellett and colleagues (see, for example, Murray et al., 1982a) have pointed out the particular relevance of this ability to the natural conditions of infection. By contrast to the artificial laboratory situation in which the virus is usually provided with cells that are partially transformed (they are immortal) and undergoing rapid growth and division, most cells encountered by the virus in the natural host are likely to be arrested at the Gl/GO boundary. Thus, it would seem to be of considerable advantage to the virus to possess a mechanism that, soon after an adenovirus enters such a relatively inactive host cell, induces that cell to enter its most active biosynthetic state and, thus, provide maximal quantities of those cellular proteins upon which viral DNA synthesis and gene expression depend. 

As mentioned in Section 2.3, some of the very first examinations of adenovirus-infected, permissive cells revealed large quantitative changes in total RNA synthesis. Subsequently, it was established that the metabolism of both cellular mRNA and rRNA are severely disrupted as a full-fledged productive infection enters the late phase. These changes, coupled with the selective translation of viral mRNA 

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