Mouse embryonic fibroblasts null for the Krueppel-like factor 4 gene are genetically unstable

• Published in: Oncogene Vol. 28; no. 9; pp. 1197 - 1205
• Main Authors: Hagos, E G, Ghaleb, A M, Dalton, W B, Bialkowska, A B, Yang, V W
• Format: Journal Article
• Language: English
• Published: 01.03.2009
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2008.465

Krueppel-like factor 4 (KLF4) is a zinc-finger transcription factor with tumor suppressive activity in colorectal cancer. Here, we investigated whether KLF4 is involved in maintaining genetic stability in mouse embryonic fibroblasts (MEFs) isolated from mice wild type (+/+), heterozygous (+/-), or homozygous (-/-) for the Klf4 alleles. Compared to Klf4 super(+/+) and Klf4 super(+/-) MEFs, Klf4 super(-/-) MEFs had both a higher level of apoptosis and rate of proliferation. Quantification of chromosome numbers showed that Klf4 super(-/-) MEFs were aneuploid. A higher number of Klf4 super(-/-) MEFs exhibited [gamma]-H2AX foci and had higher amounts of [gamma]-H2AX compared to controls. Cytogenetic analysis demonstrated the presence of numerous chromosome aberrations including dicentric chromosomes, chromatid breaks, and double minute chromosomes in Klf4 super(-/-) cells but in few, if any, Klf4 super(+/+) or Klf4 super(+/-) MEFs. Approximately 25% of Klf4 super(-/-) MEFs exhibited centrosome amplification in contrast to the less than 5% of Klf4 super(+/+) or Klf4 super(+/-) MEFs. Finally, only Klf4 super(-/-) MEFs were capable of anchorage-independent growth. Taken together, these findings demonstrate that MEFs null for the Klf4 alleles are genetically unstable, as evidenced by the presence of aneuploidy, chromosome aberration and centrosome amplification. The results support a crucial role for KLF4 in maintaining genetic stability and as a tumor suppressor.