RUNX1 transformation of primary embryonic fibroblasts is revealed in the absence of p53

Abstract

The mammalian Runx gene family (Runx1-3) are transcription factors that play essential, lineage-specific roles in development. A growing body of evidence implicates these genes as mutational targets in cancer where, in different contexts, individual family members have been reported to act as tumour suppressors, dominant oncogenes or mediators of metastasis. We are exploring these paradoxical observations by ectopic expression of RUNX genes in primary murine embryonic fibroblasts where, in common with a number of other dominant oncogenes, RUNX1 induces senescence-like growth arrest in the presence of an intact p19 ARF -p53 pathway. We now report that, in MEFs lacking functional p53, RUNX1 has apparently prooncogenic effects on cell growth that include cytoskeletal reorganization, reduced contact inhibition at confluence and accelerated tumour expansion in vivo. On the other hand, RUNX1 conferred no obvious growth advantage at low cell density and actually delayed entry of primary MEFs into S phase. We also found that ectopic RUNX1 interferes with the morphological and growth responses of p53-null MEFs to TGFb indicating that these effects are mediated by overlapping pathways. These observations help to elucidate the context-dependent consequences of loss and gain of Runx activity.

Runx2 and MYC Collaborate in Lymphoma Development by Suppressing Apoptotic and Growth Arrest Pathways In vivo

“…RUNX genes have been implicated in the control of cell cycle in both a positive and negative fashion (28)(29)(30)(31)(32). The proliferation defect observed in CD2-Runx2 transgenics parallels observations on preosteoblasts where Runx2 is required for regulating exit from the cell cycle and loss of function results in enhanced proliferation (33,34).…”

The Bone-specific Expression of Runx2 Oscillates during the Cell Cycle to Support a G1-related Antiproliferative Function in Osteoblasts

“…Runx1 is a frequent target of chromosomal translocations in acute myelogenous leukemia (60,61), and Runx3 is associated with gastrointestinal hyperplasias and stomach cancer (62,63). Thus, it has now become apparent that the entire class of Runx-related transcription factors, which encompasses Runx1/AML1, Runx2/Cbfa1 and Runx3/ PEBP2␣C, regulates cell growth in a tissue-and cell typerestricted manner (23,31,60,(63)(64)(65)(66)(67).…”

Runx1 Directly Promotes Proliferation of Hair Follicle Stem Cells and Epithelial Tumor Formation in Mouse Skin

“…Moreover, Runx1 interacts with other known cancer genes. It is downstream of p63 (42), another stem cell factor expressed at high levels in skin squamous cell carcinomas that is necessary for efficient tumor formation (68), and in a p53 mutant fibroblast line Runx1 was found to induce oncogenic transformation (67).…”