Cyclin D1 overexpression and p53 inactivation immortalize primary oral keratinocytes by a telomerase-independent mechanism
Oliver G. Opitz, … , Hubert E. Blum, Anil K. Rustgi
Oliver G. Opitz, … , Hubert E. Blum, Anil K. Rustgi
Published September 1, 2001
Citation Information: J Clin Invest. 2001;108(5):725-732. https://doi.org/10.1172/JCI11909.
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Article

Cyclin D1 overexpression and p53 inactivation immortalize primary oral keratinocytes by a telomerase-independent mechanism

Abstract

The immortalization of human cells is a critical step in multistep carcinogenesis. Oral-esophageal carcinomas, a model system to investigate molecular mechanisms underlying squamous carcinogenesis, frequently involve cyclin D1 overexpression and inactivation of the p53 tumor suppressor. Therefore, our goal was to establish the functional role of cyclin D1 overexpression and p53 inactivation in the immortalization of primary human oral squamous epithelial cells (keratinocytes) as an important step toward malignant transformation. Cyclin D1 overexpression alone was found to induce extension of the replicative life span of normal oral keratinocytes, whereas the combination of cyclin D1 overexpression and p53 inactivation led to their immortalization. This study also demonstrates that immortalization of oral keratinocytes can be independent of telomerase activation, involving an alternative pathway of telomere maintenance (ALT).

Authors

Oliver G. Opitz, Yasir Suliman, William C. Hahn, Hideki Harada, Hubert E. Blum, Anil K. Rustgi

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Figure 3

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Replicative life span of the parental and derived oral keratinocytes. (a...
Replicative life span of the parental and derived oral keratinocytes. (a) The growth characteristics of the parental and derived OKF6 cells are depicted as follows: OKF6 (circles), OKF6-D1 (triangles), OKF6-Δp53 (squares), and OKF6-D1/Δp53 (diamonds). (b) The replicative life span of OKF6, OKF6-lacZ, OKF6-D1, OKF6-Δp53, and OKF6-D1/Δp53 was assessed by calculating the PDs of each cell line. Immortalization was assessed if cells grew at least three times beyond the life span of the parental cells.