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CELL CYCLE DYSREGULATION IN ORAL CANCER

¹ Department of Oral & Maxillofacial Surgery, Massachusetts General Hospital/Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115; ² Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115; ³ Gastroenterology Division, ⁴ Department of Genetics, and ⁵ Cancer Center, University of Pennsylvania, 415 Curie Blvd., Philadelphia, PA 19104; ⁶ Department of Oral Diagnostic Sciences, Division of Oral Pathology, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115;

View larger version (83K): [in a new window]   Figure 1. Regulation of the G1 to S phase transition by the retinoblastoma suppressor protein (pRB). G0, G1, S, G2, and M refer to the quiescence, first gap, DNA synthesis, second gap, and mitosis phases of the cell cycle. CDK refers to cyclin-dependent kinases. CDC-2 refers to cell cycle control-2. Phosphorylated pRB is represented as pRB-P. Briefly, pRB-E2F transcriptional repression of genes regulating DNA synthesis is released by phosphorylation of pRB, allowing for cell cycle progression from G1 to the S phase.

View larger version (86K): [in a new window]   Figure 2. Mitogen-activated G1 transition to the S phase. Mitogen stimulation leads to cyclin D1 synthesis. Together with its catalytic partners CDK4 and CDK6, cyclin D1 accelerates G1 progression by phosphorylating pRB.

View larger version (94K): [in a new window]   Figure 3. Cell cycle block by anti-mitogenic signals. Anti-mitogenic signals stimulate cyclin-dependent kinase inhibitors (CDKi) such as p16INK4a, p21WAF1/CIP1, and p27KIP1. Conversely, mitogenic stimulation leads to reduced levels and loss of CDKi-mediated inhibition of cyclin D1/CDK complexes.

View larger version (79K): [in a new window]   Figure 4. p53 and cell cycle regulation. Metabolic stresses (such as anoxia) and DNA damage lead to elevated p53 activity, resulting in cell cycle arrest and apoptosis.

View larger version (89K): [in a new window]   Figure 5. p12DOC-1-mediated cell cycle arrest. p12DOC-1 is a CDK2-associating protein, binds to the monomeric non-phosphorylated form, and suppresses the binding to cyclin E and cyclin A. In addition, p12DOC-1 suppresses DNA replication by binding DNA polymerase-alpha/primase.

View larger version (86K): [in a new window]   Figure 6. Multistep abrogation of cell cycle regulation. Dysregulation of cell cycle progression likely requires both a direct regulatory checkpoint loss combined with a failure to activate cellular senescence, differentiation, and/or apoptotic programs. The human papillomavirus (HPV) synthesizes two proteins, E6 and E7, that abrogate the p53 and pRB pathways.