Functional analysis of the leukemia protein ELL: evidence for a role in the regulation of cell growth and survival.
The ELL gene encodes an RNA polymerase II transcription factor that frequently undergoes translocation with the MLL gene in acute human myeloid leukemia. Here, we report that ELL can regulate cell proliferation and survival. In order to better understand the physiological role of the ELL protein, we have developed an ELL-inducible cell line. Cells expressing ELL were uniformly inhibited for growth by a loss of the G(1) population and an increase in the G(2)/M population. This decrease in cell growth is followed by the condensation of chromosomal DNA, activation of caspase 3, poly(ADP ribose) polymerase cleavage, and an increase in sub-G(1) population, which are all indicators of the process of programmed cell death. In support of the role of ELL in induction of cell death, expression of an ELL antisense RNA or addition of the caspase inhibitor ZVAD-fmk results in a reversal of ELL-mediated death. We have also demonstrated that the C-terminal domain of ELL, which is conserved among the ELL family of proteins that we have cloned (ELL, ELL2, and ELL3), is required for ELL's activity in the regulation of cell growth. These novel results indicate that ELL can regulate cell growth and survival and may explain how ELL translocations result in the development of human malignancies.
The Peter MacCallum Cancer Institute, Gene Regulation Laboratory, Cancer Immunology Division, East Melbourne, 3002 Victoria, Australia.
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RW
Johnstone
M
M
Gerber
T
T
Landewe
A
A
Tollefson
W S
WS
Wold
A
A
Shilatifard
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000943:Antigens, Differentiation; D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins; D016923:Cell Death; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D016193:G1 Phase; D016195:G2 Phase; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008858:Microscopy, Phase-Contrast; D008938:Mitosis; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D010445:Peptide Elongation Factors; D010957:Plasmids / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011419:Propidium / Q000494:pharmacology; D054645:Protein Phosphatase 1; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D035602:Transcriptional Elongation Factors; D014162:Transfection; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
D000590:Amino Acid Chloromethyl Ketones; D000943:Antigens, Differentiation; D061945:Caspase Inhibitors; D018797:Cell Cycle Proteins; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; C090862:ELL protein, human; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D010445:Peptide Elongation Factors; D011506:Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D011419:Propidium; D004247:DNA; D011065:Poly(ADP-ribose) Polymerases; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases