Journal Article

KLF4, p21 and context-dependent opposing forces in cancer

Peeper, Daniel S., Rowland, Benjamin D.

2006

Overview

Krüppel-like factors are transcriptional regulators that function both as tumour suppressors and oncogenes through their control of p21 expression. This might be an important nodal point of cell control for other factors that have opposing functions in cancer. Key Points Krüppel-like transcription factors (KLFs) regulate the expression of many genes, including those that are involved in differentiation and cell-cycle arrest. One KLF family member, KLF4, possesses tumour-suppressor-like properties, as the gene that encodes it is deleted or methylated (silenced) in human gastrointestinal tract tumours. In mice, deletion of Klf4 in the gastric compartment induces hyperplasia and polyps. Ectopic expression of KLF4 induces cell-cycle arrest in a p21-dependent manner. KLF4 also seems to function as a dominant oncogene, as it is often overexpressed in human breast tumours and squamous cell carcinomas, and can also contribute to oncogenic transformation of cultured cells. Loss of p21 is sufficient to convert KLF4 from an inhibitor of proliferation into a transforming oncogene in vitro . p21 might represent a nodal point for signals from multiple factors with opposing, context-dependent functions in cancer, including transforming growth factor-β, Notch, Runx and Ras. Although CDKN1A (cyclin-dependent kinase inhibitor 1A, the gene that encodes p21) is a target gene of many key tumour-suppressor pathways, it is not often lost or mutated in human tumours. p21 itself also possesses opposing functions that might both counteract and contribute to cancer progression. Partial, but not complete, loss of p21 might provide a selective advantage to tumour cells, which could be related to the proposed roles for p21 in suppressing apoptosis and inducing cell-cycle arrest. Krüppel-like factors are transcriptional regulators that influence several cellular functions, including proliferation. Recent studies have shown that one family member, KLF4 , can function both as a tumour suppressor and an oncogene. The ability of KLF4 to affect the levels of expression of the cell-cycle regulator p21 seems to be involved, in that this protein might function as a switch that determines the outcome of KLF4 signalling. Is this role of p21 restricted to KLF4, or does p21 represent a nodal point for signals from multiple other factors with opposing functions in cancer?

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animals / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Cyclin-Dependent Kinase Inhibitor p21 - physiology / Genes, Tumor Suppressor - physiology / Genetic aspects / Humans / Kruppel-Like Transcription Factors - physiology / Mice / Neoplasms - genetics / Oncogenes - physiology / Physiological aspects / review-article / Transforming growth factors