Alterations in programmed cell death or apoptosis contribute to developmental abnormalities, autoimmune disease, and cancer. This is most clearly demonstrated by the discovery that the Bcl-2 plays a critical role in the development of B-cell lymphoma in humans. This may also be true in the case of salivary gland where the development of salivary gland tumors might involve genetic changes that stimulate proliferation and suppress apoptosis. Likewise, Sjogrens syndrome appears to involve the loss of salivary acinar cells by an autoimmune response that results in Fas-induced apoptosis. These observation suggest that understanding the signaling me3chanisms that regulate apoptosis in the salivary gland is fundamental to understanding the biology of this tissue. This proposal will focus upon two different signaling molecules, members of the MAP kinase family, and the anti-apoptotic protein kinase AKT. Based upon our data on etoposide-induced apoptosis of salivary cell lines, we hypothesize that changes in the balance between two MAP kinase family members, ERKs and JNKs, may play an important role in determining whether a cell will undergo apoptosis. We will determine whether this is also true for two other apoptotic stimuli, Fas and x-irradiation, using both established salivary acinar cell lines and primary salivary acinar cells. Dominant negative and constitutively activated mutants of different signaling molecules will be used to determine the role of ERKs and JNKs in apoptosis. We also hypothesize that activation of AKT, either by growth factor stimulation or mutation of AKT, can suppress apoptosis induced by etoposide, x-irradiation, or Fas. This will be directed tested in salivary cell lines and primary acinar cells stimulated with various growth factors, or transduced with adenoviral vectors encoding a constitutively activated mutant of AKT. Finally, transgenic mice that express a constitutively activated form of AKT in the salivary gland will be used to determine the role that AKT plays in suppressing apoptosis in this tissue. The effects of AKT expression tissue homeostasis in vivo will be assessed. Furthermore, we will examine the effects of specific apoptosis stimuli upon salivary acinar cells from these transgenic both in vitro and in vivo. These studies will provide information about pathways that regulate apoptosis in salivary acinar cells which is fundamental to our understanding of this complex tissue.
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