Cell cycle inhibitors in oral leukoplakia: A review

Main Article Content

Gokul Sridharan Kriti Bagri-Manjrekar Akhil Shankar


Cell cycle is a complex and coordinated process characterized by orderly progression in the life cycle of cells mainly orchestrated by cyclins and cyclin dependent kinases (CDK) and their inhibitors. The kinases drive the cell cycle by phosphorylating critical target proteins that are required for progression of cell to the next phase of cell cycle.  This progress is tightly regulated by a group of cell cycle inhibitors known as CDK inhibitors which may be responsible for maintenance of cell cycle and proliferation arrest once the cells’ developmental fate has been reached. Cell cycle inhibitors may act as checkpoints to identify the defective components of the cell thereby aiding in its repair and hence inactivation of these genes may interfere with the terminal differentiation thus leading to unrestricted proliferation and tumorigenesis. Cell proliferation is an important property of malignant tumor cells and dysregulation of genes governing the cell cycle is of considerable significance in the development of oral squamous cell carcinoma. Most OSCC generally develop by the malignant transformation of potentially malignant disorders the most common of which is leukoplakia. Hence evaluation of these genetic alterations in leukoplakia can be useful in assessment of the potential for malignant transformation and may also aid in attempting any therapeutic strategies at this stage. This review aims to provide data related to the role of cell cycle inhibitors in oral leukoplakia highlighting their role in malignant transformation.

Article Details

How to Cite
SRIDHARAN, Gokul; BAGRI-MANJREKAR, Kriti; SHANKAR, Akhil. Cell cycle inhibitors in oral leukoplakia: A review. Medical Research Archives, [S.l.], v. 4, n. 7, nov. 2016. ISSN 2375-1924. Available at: <http://journals.ke-i.org/index.php/mra/article/view/737>. Date accessed: 20 jan. 2018.
leukoplakia, cell cycle inhibitors, malignant transformation, CKIs
Review Articles


Agarwal S, Mathur M, Shukla NK, Ralhana R (1998). Expression of cyclin dependent kinase inhibitor p21waf1/cip1 in premalignant and malignant oral lesions: relationship with p53 status. Oral Oncology; 34:353-360

Arellano M, Moreno S (1997) Regulation of CDK/cyclin complexes during the cell cycle. Int. J. Biochem. Cell Biol; 29:559-573.

Barnes L, Eveson JW, Reichart P, Sidransky. WHO classification of tumors. Pathology and genetics. Head and neck tumors. International agency for research on cancer (IARC). Lyon, France: IARFC press 2005

Bartek J, Lukas J (2001). Pathways governing G1/S transition and their response to DNA damage. FEBS Lett; 490: 117–122.

Besson A, Dowdy SF, Roberts JM (2008). CDK inhibitors: cell cycle regulators and beyond. Developmental cell review. 159-169

Bradley KT, Budnick SD, Logani S (2006). Immunohistochemical detection of p16INK4a in dysplastic lesions of the oral cavity. Mod Pathol; 19(10):1310-1316.
Cheng T (2004). Cell cycle inhibitors in normal and tumor stem cells. Oncogene; 23:7256-7266

Classon M, Harlow E (2002). The retinoblastoma tumor suppressor in development and cancer. Nat. Rev. Cancer; 2:910–917.

Dickson MA, Schwartz GK (2009). Development of cell cycle inhibitors for cancer therapy. Current Oncol; 16(2):36-43

Kaldis P, Russo AA, Chou HS, Pavletich NP, Solomon MJ (1998). Human and yeast CDK- activating kinases (CAKs) display distinct substrate specificities. Mol Biol Cell; 9:2545-2560

Kovesi G, Szende B (2006). Prognostic value of cyclin D1 p27 and p63 in oral leukoplakia. J Oral Pathol Med; 35:274-277.

Kresty LA, Mallery SR, Knobloch TJ, Li J, Lloyd M, Casto BC, Weghorst CM (2008). Frequent Alterations of p16INK4a and p14ARF in Oral Proliferative Verrucous Leukoplakia. Cancer Epidemiol Biomarkers Prev; 17:3179-3187

Kudo Y, Kitajima S, Ogawa I, Miyauchi M, Takata T (2005). Down-regulation of Cdk inhibitor p27 in oral squamous cell carcinoma Oral Oncology; 41:105–116

Kumar, Abbas, Aster (2015). Robbins and Cotran Pathological basis of disease 9th edtn. Elsevier Publications (South Asia)

Lacy ER, Filippov I, Lewis WS, Otieno S, Xiao L, Weiss S, Hengst L,Kriwacki RW (2004). p27 binds cyclin-CDK complexes through a sequential mechanism involving binding-induced protein folding. Nat. Struct. Mol. Biol. 11, 358–364.

Li Y, Nichols MA, Shay JW, Xiong Y (1994). Transcriptional repression of the D-type cyclin dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb. Cancer Res; 54:396-403

Lundberg AS, Weinberg RA (1999). Control of the cell cycle and apoptosis. Eur J Cancer 35:1886-1894.

Morgan DO (1995). Principles of CDK regulation. Nature; 374:131-134.

Napier SS, Speight PM (2008). Natural history of potentially malignant oral lesions and conditions: an overview of the literature. J Oral Pathol Med; 37:1-10

Nasser W, Flechtenmacher C, Holzinger D, Hofele C, Bosch FX (2011). Aberrant expression of p53, p16INK4a and Ki-67 as basic biomarker for malignant progression of oral leukoplakias. J Oral Pathol Med; 40:629-635.

Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM, Pagano M (1995). Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol Cell Biol; 15:2612-2624.

R. Todd, PW. Hinds, K. Munger, AK. Rustgi, OG. Opitz, Y. Suliman, DT. Wong (2002). Cell cycle dysregulation in oral cancer Crit Rev Oral Biol Med; 13(1):51-61

Ramasubramanian A, Ramani P, Sherlin HJ, Premkumar P, Natesan A, Thiruvengadam C (2013).

Immunohistochemical evaluation of oral epithelial dysplasia using cyclin-D1, p27 and p63 expression as predictors of malignant transformation. J Nat Sci Biol Med; 4:349-58.

Shapiro GI (2006). Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol. 2006;24(11):1770-1783.

Sheppard KE, McArthur GA (2013). The cell-cycle regulator CDK4: an emerging therapeutic target in melanoma. Clin Cancer Res. 2013;19(19):5320-5328.

Sherr CJ (1994) G1 phase progression: cycling on cue. Cell; 79:551-555.

Sherr CJ, Roberts JM (1995) Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 9, 1149-1163.

Sherr CJ, Roberts JM (1999). CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev; 13:1501–1512.

Shintani S, Mihara M, Nakahara Y, Kiyota A, Ueyama Y, Matsumura T, Wong DT (2002). Expression of cell cycle control proteins in normal epithelium, premalignant and malignant lesions of oral cavity. Oral Oncol; 38(3):235-43.

Slingerland J, Pagano M (2000). Regulation of the Cdk Inhibitor p27 and Its Deregulation in Cancer. Journal of cellular physiology 183:10–17

Tsuzuki H, Fujieda S, Sunaga H, Narita N, Tokuriki M, Saito H (2003). Expression of p27 and apoptosis in oral leukoplakia. Anticancer Res; 23:1265-70.

Papadimitrakopoulou V, Izzo J, Lippman SM, Lee JS, Fan YH, Clayman G, Ro JY, Hittelman WN, Lotan R, Hong WK, Mao L (1997). Frequent inactivation of p16INK4a in oral premalignant lesions. Oncogene; 14:1799-1803

Van der Waal I (2014). Oral potentially malignant disorders: Is malignant transformation predictable and preventable? Med Oral Patol Oral Cir Bucal; 19:e386-e390

Van der Waal I, Schepman KP, Van der Meij EH, Smeele LE (1997). Oral Leukoplakia: a clinico-pathological Review. Oral Oncol; 33:291-301

Vermeulen K, Van Bockstaele DR, Berneman ZM (2003). The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell prolif; 36: 131-149

Villa A, Gohel A (2014). Oral potentially malignant disorders in a large population. J Appl Oral Sci; 22:473-476

Visioli F, Lauxen IS, Filho MS, Rados PV (2012). Expression of the cell cycle regulation proteins p53 and p21waf1 in different types of non-dysplastic leukoplakias. J Appl Oral Sci; 20(3):369-75

Warnakulasuriya S (2001). Histological grading of oral epithelial dysplasia: revisited. J Pathol; 194:294-297

Warnakulasuriya S, Johnson NW, Van der Waal I (2007). Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med; 36:575–80

Warnakulasuriya S, Reibel J, Bouquot J, Dabelsteen E (2008). Oral epithelial dysplasia classification systems: predictive value, utility, weaknesses and scope for improvement. J Oral Pathol Med; 37: 127-133

Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D. p21 is a universal inhibitor of cyclin kinases. Nature 1993; 366:701-704.

Most read articles by the same author(s)

Obs.: This plugin requires at least one statistics/report plugin to be enabled. If your statistics plugins provide more than one metric then please also select a main metric on the admin's site settings page and/or on the journal manager's settings pages.