DNA methylation abnormalities occur consistently in human neoplasia including widespread hypomethylation and more recently recognized local increases in DNA methylation that hold potential for gene inactivation events. To study this imbalance further, we have cloned and localized to chromosome 19 a portion ofthe human DNA methyltransferase gene that codes for the enzyme catalyzing DNA methylation.
We have investigated the regulation of urokinase (u‐PA) mRNA in quiescent mouse fibroblasts and keratinocytes stimulated to divide by the addition of serum or epidermal growth factor (EGF), respectively. Serum stimulation of quiescent fibroblasts (BALB/c 3T3 or Swiss 3T3) results in an early and transient increase of u‐PA mRNA level, which precedes by several hours the onset of DNA synthesis. A similar response is elicited by EGF stimulation of quiescent keratinocytes. The increase of u‐PA mRNA parallels that of c‐myc mRNA, does not require protein synthesis and is at least in part due to increase in template activity of the u‐PA gene. Induction of terminal differentiation of mouse keratinocytes results in a decrease of u‐PA mRNA which parallels the decrease of thymidine incorporation. In conclusion, variation in the level of u‐PA mRNA is seen during G0/G1 transition and correlates with the proliferative state of these normal mouse cells.
Investigations of the pathways regulating normal growth of epithelial cells have revealed the existence of two major growth-factor signaling cascades required for proliferation. One pathway is activated by IGF-1 or high insulin concentration. The other is triggered by EGF, TGF alpha, or members of the FGF family, including the recently discovered epithelial-cell-specific growth factor, designated keratinocyte growth factor (KGF). Its expression pattern in vivo suggests that KGF plays an important normal physiologic role as a stromal effector of epithelial cell proliferation. Oncogenes, which represent constitutively activated forms of genes critically involved in growth-factor signaling pathways, specifically abrogate the requirement for mitogens of the EGF pathway. Examples of such genes include the erbB/EGF receptor and erbB-2, which encode structurally related receptor proteins and are often amplified and/or overexpressed in epithelial malignancies. Employing reduced stringency hybridization with v-erbB as a probe, we recently identified a third member of this receptor family, designated erbB-3. cDNA cloning revealed a predicted 148-kD transmembrane polypeptide with structural features similar to those of the EGF receptor. Normal erbB-3 expression in keratinocytes and glandular epithelium suggests its physiologic role in these cell types. Moreover, markedly elevated erbB-3 mRNA levels in certain mammary tumor cell lines suggest that increased erbB-3 expression may also play a role in some human epithelial malignancies.
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