Histone methyltransferase MLL1 regulates MDR1 transcription and chemoresistance.

The multidrug resistance 1 gene (MDR1) encodes P-glycoprotein (Pgp), a member of the ATP-binding cassette (ABC) transporter family that confers tumor drug resistance by actively effluxing a number of antitumor agents. We had previously shown that MDR1 transcription is regulated by epigenetic events such as histone acetylation, and had identified the histone acetylase P/CAF and the transcription factor NF-Y as the factors mediating the enzymatic and DNA-anchoring functions, respectively, at the MDR1 promoter. It has also been shown that MDR1 activation is accompanied by increased methylation on lysine 4 of histone H3 (H3K4).

E2F-1 overexpression in U2OS cells increases cyclin B1 levels and cdc2 kinase activity and sensitizes cells to antimitotic agents.

The E2F transcription factors play a critical role in coordinating transcription of specific genes essential for G1-S transition. In early G1, the retinoblastoma protein (pRB) becomes phosphorylated by cyclin-dependent kinases, disrupting pRB binding to E2F-1-3, allowing "free" E2F to regulate genes involved in proliferation. In the present study, we used a tetracycline E2F-1 inducible U2OS osteosarcoma cell line to investigate the effect of increasing levels of E2F-1 on the cytotoxicity of various chemotherapeutic drugs.

p14ARF expression increases dihydrofolate reductase degradation and paradoxically results in resistance to folate antagonists in cells with nonfunctional p53.

The p14(ARF) protein, the product of an alternate reading frame of the INK4A/ARF locus on human chromosome 9p21, disrupts the ability of MDM2 to target p53 for proteosomal degradation and causes an increase in steady-state p53 levels, leading to a G(1) and G(2) arrest of cells in the cell cycle. Although much is known about the function of p14(ARF) in the p53 pathway, not as much is known about its function in human tumor growth and chemosensitivity independently of up-regulation of p53 protein levels. To learn more about its effect on cellular proliferation and chemoresistance independent of p53 up-regulation, human HT-1080 fibrosarcoma cells null for p14(ARF) and harboring a defective p53 pathway were stably transfected with p14(ARF) cDNA under the tight control of a doxycycline-inducible promoter.