Oncogene
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The Wilms' tumor 1 gene (WT1) encodes a transcription factor of the zinc-finger family and is homozygously mutated or deleted in a subset of Wilms' tumors. Through alternative mRNA splicing, the gene is expressed as four main polypeptides that differ by a stretch of 17 amino acids just N-terminal of the four zinc-fingers and three amino acids between zinc fingers 3 and 4. We have previously shown that expression of the WT1(-/-) isoform, lacking both inserts, increases the tumor growth rate of the adenovirus-transformed baby rat kidney (AdBRK) cell line 7C3H2, whereas expression of the WT1(-/+) isoform, lacking the 17aa insert, strongly suppresses the tumorigenic phenotype. ⋯ Ectopic expression of EGR-1 in the 7C3H2 AdBRK cells significantly increases their in vivo growth rate and nullifies the tumor suppressor activity of the WT1(-/+) protein. Furthermore, we find that EGR-1 levels are elevated in some Wilms' tumors. These data are the first to show that EGR-1 overexpression causes enhanced tumor growth and that WT1 and EGR-1 exert antagonizing effects on growth regulation in baby rat kidney cells, which might reflect the situation in some Wilms' tumors.
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The cell cycle is governed by cyclin dependent kinases (cdks), which are activated by binding of cyclins, inhibited by cdk inhibitors and regulated by phosphorylation and dephosphorylation. Exposure to high dose dihydrotestosterone (DHT) inhibits population growth of the human prostate carcinoma cell line, LNCaP. To determine the mechanism of growth arrest by high dose DHT, we assayed the changes in cell cycle profile and the cell cycle regulators that mediate these effects. ⋯ Inhibition of these G1 cyclin dependent kinases was not due to loss of either cyclin or cdk proteins nor to increases in the cdk inhibitors p16INK4A and p21CiP1. p21Cip1 protein levels remained constant, and cyclin E-associated p21CiP1 fell, suggesting that p21CiP1 is not relevant to this form of cyclin E/cdk2 inhibition. Of note, total p27KiP1 levels and cyclin E-associated p27Kip1 increased as cells arrested and the amount of the CAK activated cdk2 bound to cyclin E decreased. p27KiP1 immunodepletion experiments demonstrated that the DHT-mediated increase in p27Kip1 was sufficient to fully saturate and inhibit target cyclin E/ cdk2. The inhibition of cyclin E/cdk2 by p27Kip1 contributes to G1 arrest of LNCaP following high dose DHT. p27KiP1 may be a key effector of androgen dependent growth modulation in prostate cancer cells.