p16(INK4a) Prevents Centrosome Dysfunction and Genomic Instability in Primary Cells

Aneuploidy, frequently observed in premalignant lesions, disrupts gene dosage and contributes to neoplastic progression. Theodor Boveri hypothesized nearly 100 years ago that aneuploidy was due to an increase in centrosome number (multipolar mitoses) and the resultant abnormal segregation of chromosomes. We performed immunocytochemistry, quantitative immunofluorescence, karyotypic analysis, and time-lapse microscopy on primary human diploid epithelial cells and fibroblasts to better understand the mechanism involved in the production of supernumerary centrosomes (more than two microtubule nucleating bodies) to directly demonstrate that the presence of supernumerary centrosomes in genomically intact cells generates aneuploid daughter cells. We show that loss of p16(INK4a) generates supernumerary centrosomes through centriole pair splitting. Generation of supernumerary centrosomes in human diploid epithelial cells was shown to nucleate multipolar spindles and directly drive production of aneuploid daughter cells as a result of unequal segregation of the genomic material during mitosis. Finally, we demonstrate that p16(INK4a) cooperates with p21 through regulation of cyclin-dependent kinase activity to prevent centriole pair splitting. Cells with loss of p16(INK4a) activity have been found in vivo in histologically normal mammary tissue from a substantial fraction of healthy, disease-free women. Demonstration of centrosome dysfunction in cells due to loss of p16(INK4a) suggests that, under the appropriate conditions, these cells can become aneuploid. Gain or loss of genomic material (aneuploidy) may provide the necessary proproliferation and antiapoptotic mechanisms needed for the earliest stages of tumorigenesis

IER5, a dna damage response gene, is required for notch-mediated induction of squamous cell differentiation

Notch signaling regulates squamous cell proliferation and differentiation and is frequently disrupted in squamous cell carcinomas, in which Notch is tumor suppressive. Here, we show that conditional activation of Notch in squamous cells activates a context-specific gene expression program through lineage-specific regulatory elements. Among direct Notch target genes are multiple DNA damage response genes, including IER5, which we show is required for Notch-induced differentiation of squamous carcinoma cells and TERT-immortalized keratinocytes. IER5 is epistatic to PPP2R2A, a gene that encodes the PP2A B55α subunit, which we show interacts with IER5 in cells and in purified systems. Thus, Notch and DNA-damage response pathways converge in squamous cells on common genes that promote differentiation, which may serve to eliminate damaged cells from the proliferative pool. We further propose that crosstalk involving Notch and PP2A enables tuning and integration of Notch signaling with other pathways that regulate squamous differentiation

The Relationship of Tobacco, Alcohol, and Betel Quid with the Formation of Oral Potentially Malignant Disorders: A Community-Based Study from Northeastern Thailand

This study’s objective was to describe the relationship between the main risk factors for oral cancer, including tobacco (in the form of cigarettes, smokeless tobacco (SLT), secondhand smoking (SS)), alcohol, and betel quid (BQ), and the occurrence of oral potentially malignant disorders (OPMDs). A community-based case-control study was conducted with a population of 1448 adults aged 40 years or above in northeastern Thailand. Patients aged 60 years or above (OR 1.79, p < 0.001) and female patients (OR 2.17, p < 0.001) had a significant chance of having OPMDs. Our multivariate analysis showed that the most potent risk factor for OPMDs occurrence was betel quid (BQ) (adjusted OR 4.65, p < 0.001), followed by alcohol (OR 3.40, p < 0.001). Even former users were at risk of developing OPMDs. The synergistic effect between these main risk factors was significantly shown in the group exposed to SLT, SS, BQ, and alcohol. The most potent synergistic effect was found in the group exposed to SLT, BQ and alcohol with the OR = 20.96