Potential role of cyclin D₁in DNA damage response

Background

In mammalian cells, cell cycle progression is governed by distinct cyclin-dependent kinases (cdks) whose activities are regulated by binding of their activating cyclin subunits and through negative regulation by inhibitor proteins such as p21. Cyclin levels oscillate in a phase-dependent manner, ensuring the stage-specific activation of cyclin/cdk complexes. The D-type cyclin levels are thought to act as sensors of the cellular environment: under conditions permissive for proliferation, D-type cyclins accumulate and facilitate the G₁ phase progression; whereas under restrictive conditions, D-type cyclin transcription is attenuated and the protein is destabilised via ubiquitin-mediated proteolysis. In addition to the normal cell cycle regulation, a member of D-type cyclins, cyclin D₁, has been implicated in the DNA damage response. Once activated, DNA damage responses disrupt the function of the cell cycle and can result in a number of outcomes including short-term or long-term cell cycle arrest, apoptosis and necrosis. Cyclin D₁ expression is often found deregulated in cancerous cells, particularly in those of the breast and the head/neck.

Results

Preliminary data showed that the expression of cyclin D₁ responds to the DNA damage induced by an environmental carcinogen, 4-nitroquinoline 1-oxide (4NQO), in a biphasic manner. At a low level (2.5 μM), the cyclin D₁ level is unchanged but p21 is induced strongly after 3 hours; at intermediate levels (10–50 μM), there is a dramatic reduction in the level of cyclin D₁ while p21 fails to accumulate; at high levels (100–200 μM), little change in cyclin D₁ or p21 is observed. The cellular responses associated with different 4NQO doses analysed by flow cytometry will be presented.

Conclusion

Our findings suggest that the level of cyclin D₁ following the DNA damage induced by 4NQO may play a role in dictating the outcome of the cellular response. Our ongoing research aims to compare and contrast the cellular responses linked to various specific DNA damaging agents in terms of cell cycle regulatory proteins, focusing on cyclin D₁, and ultimately to understand the molecular mechanisms underlying the regulation of such responses.