PROTEIN KINASE C IN THE LENS

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All tissues must accommodate stress and growth signals in order to survive. The lens must also function under natural hypoxia, a condition which is so detrimental in heart and brain that one result is ischemic stroke. Ischemic damage is propagated through the gap junction protein, Cx43, and it is protein kinase C (PKC) epsilon which provides protection from damage in heart (1). In contrast, we have found that the lens contains two stress switch PKC isoforms, PKC gamma (PKCγ) and PKC epsilon (PKCε), which both play a stress protection role in the lens (2). During oxidative stress the PKCγ may function to inhibit gap junction proteins, Cx43, Cx50 and Cx46. In contrast, the PKCε is activated by hypoxia and is always found in the mitochondria. The long-term objective of our research is to determine how PKCs protect the lens from cataract formation. PKCγ and PKCε are both part of a large group of stress-switch C1B-containing proteins. C1B domains are zinc-finger/cysteine-rich domains which can be activated by cellular regulatory signals. The overall hypothesis of this proposal is: The lens, which thrives under natural hypoxia, contains two stressswitch PKC isoforms, PKCγ and PKCε, which provide protection during differentiation, hypoxia, and oxidative stress. We have previously reported that oxidative stress signals, such as hydrogen peroxide or the growth factor, IGF-1, activate lens PKCγ and cause the inhibition of the gap junction proteins, Cx43, Cx50, and Cx46, and protection of the lens from oxidative stress and cataracts. In contrast, we find that PKCε is not activated under these same conditions but is activated only by hypoxia (2). The hypoxia-driven activation of PKCε results in translocation to the lens mitochondria and activation of lens mitochondrial cytochrome C oxidase IV (cytIV) and in increased cytIV activity (3). We hypothesize that hypoxia induced activation of cytIV may help to prevent mitochondrial-driven apoptosis which could normally occur under hypoxic conditions in the differentiating lens. Thus, these two PKC isoforms protect the lens through phosphorylation of their respective targets, gap junction proteins (PKCγ targets) and mitochondrial cytIV (PKCε target).