EFFECTS OF IONIZING IRRADIATION AND BETA-ADRENERGIC STIMULATION ON GENE-EXPRESSION PATTERN IN RAT SUBMANDIBULAR GLANDS

Radiotherapy administrated to patients with head and neck malignancies and prior to bone marrow transplantation often results in severe xero stomia. We evaluated the expression of early response proto-oncogenes (c-fos and jun B), tissue specific genes (proline rich protein [PRP] a nd kallikrein), and proteolysis linked utiquitin gene following exposu re to 15 Gy irradiation alone or in combination with beta-adrenergic s timulation of the rat submandibular glands. Head and neck irradiation resulted not only in dysfunction and tissue loss of the salivary gland s but also in a systemic effect expressed as profound body weight loss . Irradiation alone was found to induce expression of the jun B but no t the c-fos proto-oncogenes. The combination of irradiation and beta-a drenergic stimulation by isoproterenol induced earlier expression of j un B and profound expression of the c-fos proto-oncogene in comparison to irradiation alone. In contrast, the kallikrein and ubiquitin genes was expressed constitutively and were not affected by irradiation alo ne or in combination with beta-adrenergic stimulation. In addition irr adiation had no effect on submandibular gland mRNA translation. We obs erved that the expression of the genes whose regulation is associated with DNA damage (i.e. jun B and c-fos) was enhanced by irradiation alo ne or in combination with isoproterenol administration. In contrast, t he expression of genes associated with the routine functional integrit y of the cell (i.e. kallikrein, ubiquitin, and PRP) was unaffected. Th ese findings, in addition to delayed gland dysfunction, leads us to be lieve that the irradiation induced injury to the submandibular glands is to be attributed to reproductive stem cell death which may be partl y obliterated in the clinical setting by better understanding.