Parin Patel

SIRT1 is a mammalian homolog of the Saccharomyces cerevisiae chromatin silencing factor Sir2. Dominant-negative and overexpression studies have implicated a role for SIRT1 in deacetylating the p53 tumor suppressor protein to dampen apoptotic and cellular senescence pathways. To elucidate SIRT1 function in normal cells, we used gene-targeted mutation to generate mice that express either a mutant SIRT1 protein that lacks part of the catalytic domain or has no detectable SIRT1 protein at all. Both types of SIRT1 mutant mice and cells had essentially the same phenotypes. SIRT1 mutant mice were small, and exhibited notable developmental defects of the retina and heart, and only infrequently survived postnatally. Moreover, SIRT1-deficient cells exhibited p53 hyperacetylation after DNA damage and increased ionizing radiation-induced thymocyte apoptosis. In SIRT1-deficient embryonic fibroblasts, however, p53 hyperacetylation after DNA damage was not accompanied by increased p21 protein induction or DNA damage sensitivity. Together, our observations provide direct evidence that endogenous SIRT1 protein regulates p53 acetylation and p53-dependent apoptosis, and show that the function of this enzyme is required for specific developmental processes.

Gingivobuccal cancer (GBC) is the most common oral cavity cancer (OCC). Its incidence is increasing with increased use of tobacco and areca nut chewing in third world countries especially the Indian subcontinent. It comprises buccal mucosa, gingivobuccal sulcus, alveolus and retromolar area cancers. OCCs comprise 12% of all male cancers in India, 40% of these are GBCs. Certain precancerous conditions and lesions such as submucous fibrosis, leukoplakia and erythroplakia are known. In special situations such as trismus, examination and early detection becomes difficult. Computed tomography scan is an investigation of choice. Tumor node metastasis staging gives adequate information for treatment selection and prognosis. Surgery remains the mainstay of curative treatment. Due to its unique proximity to mandible and posteriorly infratemporal fossa, extent of surgery remains critical to provide cure with satisfactory functional and esthetic outcomes. Marginal mandibulectomy has consistently provided these results in carefully selected patients. More advanced cancers need segmental or hemimandibulectomy and appropriate reconstruction-preferably free microvascular bone and soft-tissue transfer. Radiotherapy is used in adjuvant setting to reduce locoregional recurrences. It can also be used as palliative modality in advance cases. The role of chemotherapy is investigational; however, criteria have been defined for its use concurrent with radiation in adjuvant postoperative settings in high-risk patients. Cure rates are as high as 85% in early stages and as low as 0%–20% in advance stages. Follow-up strategy is aimed at detection of locoregional failure initially and prevention and management of second cancers.