Radiation-induced salivary gland dysfunction results from p53-dependent apoptosis.
OBJECTIVE
Radiotherapy for head-and-neck cancer causes adverse secondary side effects in the salivary glands and results in diminished quality of life for the patient. A previous in vivo study in parotid salivary glands demonstrated that targeted head-and-neck irradiation resulted in marked increases in phosphorylated p53 (serine(18)) and apoptosis, which was suppressed in transgenic mice expressing a constitutively active mutant of Akt1 (myr-Akt1).


METHODS
Transgenic and knockout mouse models were exposed to irradiation, and p53-mediated transcription, apoptosis, and salivary gland dysfunction were analyzed.


RESULTS
The proapoptotic p53 target genes PUMA and Bax were induced in parotid salivary glands of mice at early time points after therapeutic radiation. This dose-dependent induction requires expression of p53 because no radiation-induced expression of PUMA and Bax was observed in p53-/- mice. Radiation also induced apoptosis in the parotid gland in a dose-dependent manner, which was p53 dependent. Furthermore, expression of p53 was required for the acute and chronic loss of salivary function after irradiation. In contrast, apoptosis was not induced in p53-/- mice, and their salivary function was preserved after radiation exposure.


CONCLUSIONS
Apoptosis in the salivary glands after therapeutic head-and-neck irradiation is mediated by p53 and corresponds to salivary gland dysfunction in vivo.
Avila
Jennifer L
JL
Department of Physiological Sciences, University of Arizona, Tucson, AZ, USA.
Grundmann
Oliver
O
Burd
Randy
R
Limesand
Kirsten H
KH
D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3 / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation; D005260:Female; D016158:Genes, p53 / Q000235:genetics; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010306:Parotid Gland / Q000378:metabolism / Q000528:radiation effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012469:Salivary Glands / Q000378:metabolism / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D008565:Membrane Proteins; C488588:PUMA protein, mouse; C406964:Perp protein, mouse; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3