Cyclin D1 and P27KIP1: The Gatekeepers of Dysplasia

Abstract

There is increasing evidence suggesting that cyclins, cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CDIs) either are themselves targets for genetic change in cancer or are disrupted secondarily by other oncogenic events. Cyclin D1 and p27 KIP1 are two important regulators at the G1/S checkpoint. Cyclin D1 is an oncogene of cell cycle regulation with positive effect. Normally, cyclin D1 at G1 is constant or at a very low level and its excessive expression may be associated with the disordered proliferation of cells leading to malignant change. On the other hand, p27 KIP1 is an anti-oncogene for cell cycle regulation, which functions as a negative regulator. Under the regulation of TGF-β, p27 KIP1 inhibits the activity of oncogenes and controls the transition of the G1/S phase mainly by the interaction with CDK and CDK-Cyclin in order to inhibit cell proliferation and give cells opportunities to repair DNA. In addition, p27 KIP1 not only acts as CDK inhibitor, but also promotes cell differentiation and induces the apoptosis of cells. In this article we review studies that have explored the effects of cyclin D1 and P27 KIP1 on cancer progression and dysplasia with a specific focus on oral dysplasia and oral squamous cell carcinoma (OSCC). We also aim to shed some light on the different means of evaluating the interaction between Cyclin D1 and P27 KIP1 as well as the immunohistochemical reactions associated with different forms of cyclin D1. CELL CYCLE The cell cycle is the series of events that are required to create two daughter cells from a progenitor cell. The cell division cycle consists of four phases, i.e. G1, S, G2, and M. A cell that is not in the cell cycle is in a quiescent state named G0. G1 is the interval before DNA replication, S is the DNA replication phase, G2 is the interval after DNA replication, M is the mitotic phase. Progression through the cell cycle is governed by a family of cyclin-dependent kinases (CDKs), the activity of which is regulated by phosphorylation 1 , activated by binding of cyclins 2 , and inhibited by CDK inhibitors 3. The orderly progression through the different phases is assured by proteins that regulate critical checkpoints. Several checkpoints have been identified such as the late G1 phase restriction point, the G1/S phase transition, and the G2/M phase transition. These checkpoints normally verify that the preceding events have been completed before progressing to the next monitor completion of DNA replication and produce signals that interrupt the cell cycle in the event of an error or damage to the genome. Abnormal functioning of checkpoints, such as incapacity in detecting damaged DNA, may play a significant role in tumour progression by permitting cells to progress through the cell cycle with damaged or abnormal DNA 4 .