Marine virus commandeers cell cycle. A possible novel strategy for future cancer therapy?

A review of: Lui J. et al (2011) Virus infection disturbs cyclin expression, leading to cell cycle arrest in the unicellular marine algae Emiliania huxleyi and Chrysochromulina ericina. African Journal of Microbiology Research, Vol. 5 (14). P1801-1807.

Viral infections are significant in shaping marine environments by regulating succession and composition of phytoplankton communities, and crucial in their role in releasing dissolved organic matter into seawater. The importance of viruses is further emphasized by their sheer abundance suggesting a critical part in oceanic processes. Some viruses depend on the cell cycle of the host while others do not. Lui, J. et al (2001) believe that understanding the mechanisms of cell cycle arrest induced by viruses in phytoplankton hosts can help explain host-virus interactions as well as describe how viral activity is regulated in natural ecosystems.

Emiliania huxleyi is ubiquitous in the marine environment and can form blooms in coastal and oceanic waters while Chrysochromulina ericina can be found in much lower densities. Large double stranded viruses specific to E. huxleyi (EhV) and C. ericina (CeV) have been shown to cause cell cycle arrest and delay in mitosis (M phase) entry.

EhV was shown to inhibit the CDC2/cyclin B complex by phosphorylating Y15 (tyrosine in 15^th position in the amino acid secondary structure)thus blocking the active site of the mitogen promoting factor complex (MPF). There is also evidence of phosphorylation of other amino acids close to Y15. In sequence, WEE1 and CAK1 (seriously) phosphorylates Y15 and T161 (threonine at position 161) respectively. CDC25 then dephosphorylates Y15, resulting in the activation of CDC2/Cyclin B complex and subsequent progression through the G₂/M checkpoint. An increase in WEE1 proteins and deactivation of CDC25 was detected in the EhV infected cells but not in the control. The authors hypothesise that cell cycle arrest in EhV infection is to maximize viral progeny output, and in order to exert control it is necessary for the virus to block host cell cycle control mechanisms.

CeV infection decreased CDC2/cyclin B complex formation by reducing cyclin B levels while over-expressing CDC2, causing G₂ cell cycle delay. Active CDC2 was only detected late in the cell cycle of control samples, while active CDC2 was detected throughout the cell cycle in infected cells. A decrease in WEE1 protein levels was also detected. An active CDC2 and no detectable cyclin B in CeV infection suggests CDC2 (modified or unmodified) had acquired a partner protein, possibly of viral origin. The authors theorize that CeV has adopted a strategy of early cellular activation in order to facilitate viral replication at the expense of host DNA replication.

Algal host-virus interactions regulate growth dynamics of primary producers and differences in cell cycle manipulation in response to viral infection may be related to ecological strategies of the host, the virus, or both. Furthermore, it is unclear whether it is the host ecology (abundance, growth rate etc.) that dictates the interaction or whether it is the virus that determines host ecology. The authors conclude that the results indicate interactions between host and virus is optimized to maintain sustainable populations of both host and virus while avoiding extinction.

Proteins associated with cell cycle progression have been thoroughly studied in phytoplankton, showing homology and highly conserved functional domains to counterparts in other organisms. This was further reinforced by the use of commercially available antibodies for the detection of G₂/M regulatory proteins, indicating similar mechanisms between the phytoplankton and in higher eukaryotes.

In cancer studies, the defining characteristic of the p53 tumour suppressor protein (‘guardian of the genome’) is to arrest/delay the cell cycle at checkpoints during abnormal cell proliferation, which when rendered non-functional, has been implicated in over 50% of cancer cases in humans. The strategies used by EhV and CeV are similar in effect to p53 but most likely through a completely different cellular process. Cancer cells are defined by unregulated cell proliferation and a greater understanding of the molecular mechanisms behind viral induced cell cycle disruption by EhV and CeV may provide a novel strategy for tumour site directed cancer therapy in the future.