ReviewProtein kinases and their involvement in the cellular responses to genotoxic stress
Introduction
Throughout their life cycle, cells are constantly subjected to many and varied stressors. These stressors include starvation, infection, changes in their physical or chemical condition (for example, heat, cold, or pH), and genotoxic damage. Stress can be generated by both endogenous and exogenous sources. Endogenous sources would include the products of oxidative metabolic reactions, while exogenous sources could include ultraviolet (UV) light, ionizing radiation (IR), and DNA-damaging chemicals. To ensure normal growth control and accuracy in DNA replication, cells have developed a variety of responses to stress, and several signal transduction pathways function to execute these responses. Although the mechanisms underlying are incompletely understood, it is clear that the network of responses is very complex. Currently, many studies in multiple disciplines are seeking to explore and elucidate the mechanisms of the cellular responses to stress, resulting in the definition of some of the signal transduction pathways and cellular components (reviewed in [1], [2], [3], [4], [5]).
The cellular targets of stressors are primarily proteins and DNA. The heat shock response is probably the most studied cellular event that copes with protein-damaging stresses. Following a stress such as heat, several heat shock proteins (HSPs) are mobilized. These HSPs protect functional proteins from irreversible denaturation caused by heat and other stresses and assist them in renaturation. Other mechanisms, such as the son of sevenless (SOS) response in prokaryotes and the DNA repair system in eukaryotes, are used to deal with DNA-damaging stresses such as IR. Genotoxic stress, or damage to DNA, is regularly encountered by cells. Such stress can be induced by exposure to UV- or γ-irradiation, environmental chemicals or therapeutic reagents. Exposure of cells to such genotoxic agents initiates a series of events leading to the activation of a wide group of genes with diverse functions [6], [7]. Among these are a group of transcription factors as well as other gene products that can also be rapidly induced in response to mitogenic stimulation. Their dual functions illustrate the commonalities of the pathways involved in mediating the cellular responses to stress and to proliferative signals.
Given the large number of agents that damage DNA, the diversity of these agents with respect to their structures and mechanisms of action, and their ability to inflict damage on cellular components other than DNA, it is not surprising that the genotoxic response is a very complex process, involving multiple signaling pathways that exist in parallel and “cross-talk” with each other to mediate the final outcome. To simplify the issue, the cellular response to genotoxic stress can be divided into three major components [8]:
- (1)
Damage-sensing and signal-initiating events: The damage inflicted by genotoxic stress, mainly to the DNA, acts as the initiating signal. Several “sensors” then perceive the damage and initiate subsequent events.
- (2)
Signal transduction: The signal from the sensors is passed down through a number of signal transduction pathways, which are composed primarily of protein kinases that are activated through phosphorylation. This then leads to the activation of transcription factors, which in turn enhances the expression of certain genes that are involved in events such as DNA repair, cell cycle arrest, or cell death.
- (3)
Biological consequences and attenuation of the response: For a unicellular organism, repair of damaged DNA is the best way to ensure survival. Even if some damage is not repaired, the cell may still be able to continue functioning and even replicating. In metazoans, however, the optimal strategy to deal with DNA damage is not as simple, as survival of the organism may be enhanced by the loss of cells otherwise viable but with damaged DNA. Mutations in genes that are important in controlling cell growth, differentiation, and proliferation are the major cause of neoplasms which can lead to death of the organism. Therefore, it may be safer for the organism as a whole to eliminate the damaged cells. As a result, repair, growth arrest, and cell suicide (apoptosis) are all possible outcomes of the cellular response to genotoxic stress in metazoans, and the choice will depend on the cell type, location, environment, and extent of damage [9]. The activation of signal transduction pathways also enhances the expression of certain genes that can attenuate the response. For example, the protein kinase cascade activates the expression of certain phosphatases. Also, the tumor suppressor p53 protein, as a transcription factor, also activates the expression of mouse double minute 2 (MDM2), an intracellular regulator of ubiquitin-mediated degradation of p53. Therefore, a negative feedback regulation system exists in the cellular response to genotoxic stress.
Some of the key players involved in these events are well defined. One classic example is p53, which has such an important role in the genotoxic stress response that it has been called the “universal sensor for genotoxic stress” [10], [11]. Other molecules are also emerging as important regulators of the genotoxic response and have gained increasing recognition in the past several years. One such example is ceramide, a member of the sphingolipid family [12], [13]. In this review, we focus on the protein kinases and the roles they play in damage sensing and signal transduction, and finally, the attenuation of the kinases.
Section snippets
DNA damage as the initiation signal
Evidence accumulated over the years indicates that DNA damage is the most important signal for the induction of the genotoxic stress responses [14], [15], [16]. For example, DNA double-strand breaks (DSBs) can be induced by IR or other genotoxic agents, or even during the V(D)J recombination of immune system, and this can lead to activation of DNA-dependent protein kinase (DNA-PK) [17]. Direct damage to DNA, especially in the form of strand breaks, also activates the tumor suppressor p53
The downstream protein kinase cascade
To date, multiple signal transduction pathways have been shown to be involved in the cellular response to genotoxic stress, and additional components are constantly being identified. Most of these pathways involve the activation of protein kinases, which include the non-receptor tyrosine kinase c-Abl [89], Lyn [90], [91], [92], [93], and members of the mitogen-activated protein kinase (MAPK) family [94], [95], [96], [97], [98]. These kinases play a key role in the activation of transcription
Biological consequences and regulation of the kinases
As mentioned earlier, the activation of signal transduction pathways by genotoxic stress leads to several possible outcomes, such as cell cycle arrest, which allows repair of the damaged DNA, or when the damage is too severe and cannot be repaired, apoptosis. However, a key issue remain unsolved is how the cell decides if the damage is severe enough and thus to shift from repair to apoptosis. Although no plausible mechanism has been proposed, it seems likely that those DNA damage sensors (such
Conclusions
The cellular response to genotoxic stress is a very complex process. It begins with the detection of DNA damage and ends with DNA repair or cell death, and involves numerous components in multiple signal transduction pathways. A general scheme is that several sensors detect the DNA damage caused by genotoxic agents, and this signal triggers signal transduction pathways, in which the MAPK pathways play the most prominent role. This then leads to the activation of transcription factors, resulting
Acknowledgements
We the authors gratefully thank Dr. D. DeMarini and the anonymous reviewers for their valuable suggestions that greatly improved this manuscript.
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