Overexpression of cyclin D1 is associated with the decondensation of chromatin during den-induced sequential hepatocarcinogenesis.

Abstract

D-type cyclins regulate distinct cellular processes such as mitotic cell cycle control, differentiation and transcription. Deregulation of cyclin D1, a component of G1 checkpoint control, can result in enhanced genomic instability, cell transformation, and malignant neoplasia. However, a precise understanding of the molecular and cellular events underlying the regulation of the cyclin D1 gene remains to be elucidated. In this study, we examined the regulation of the cyclin D1 gene during n-nitrosodiethylamine (DEN)-induced sequential liver carcinogenesis. Northern blot studies showed an increase in the level of cyclin D1 mRNA. Southern blot analysis of the DNA restriction fragment showed no alterations and/or amplification in the coding region of the cyclin D1 gene. Bulk chromatin from DEN-treated rat liver is much more sensitive to nuclease digestion than that from normal liver. Increased expression of the cyclin D1 gene is correlated to the upregulation of its transcription, mediated through chromatin decondensation during sequential hepatocarcinogenesis. Thus, the functional inter-relationship between chromatin organization and gene expression appears to be of critical importance for liver tumour development.