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* Departments of Radiation Oncology and Pharmacology and the Ireland Comprehensive Cancer Center, Laboratory of Molecular Stress Responses, Case Western Reserve University, Cleveland, Ohio 44106-4942, USA;
Department of Pharmacology and University of Wisconsin Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin 53792, USA; and
DeRoche Discovery Welwyn, Welwyn Garden City, Hertfordshire AL7 3AY, United Kingdom
1Correspondence: Departments of Radiation Oncology and Pharmacology and the Ireland Cancer Center, Laboratory of Molecular Stress Responses, Case Western Reserve University, 10900 Euclid Ave. (BRB 326), Cleveland, OH 44106-4942, USA. E-mail: dab30{at}po.cwru.edu
Regulation of transcriptional responses in growth-arrested human cells
under conditions that promote potentially lethal damage repair after
ionizing radiation (IR) is poorly understood. Sp1/retinoblastoma
control protein (RCP) DNA binding increased within 30 min and peaked at
2–4 h after IR (450–600 cGy) in confluent radioresistant human
malignant melanoma (U1-Mel) cells. Increased phosphorylation of Sp1
directly corresponded to Sp1/RCP binding and immediate-early gene
induction, whereas pRb remained hypophosphorylated. Transfection of
U1-Mel cells with the human papillomavirus E7 gene abrogated Sp1/RCP
induction and G0/G1 cell cycle checkpoint
arrest responses, increased apoptosis and radiosensitivity, and
augmented genetic instability (i.e., increased polyploidy cells) after
IR. Increased NF-
B DNA binding in U1-Mel cells after IR treatment
lasted much longer (i.e., >20 h). U1-Mel cells overexpressing
dominant-negative IB
S32/36A mutant protein were significantly
more resistant to IR exposure and retained both G2/M and
G0/G1 cell cycle checkpoint responses without
significant genetic instability (i.e., polyploid cell populations were
not observed). Nuclear p53 protein levels and DNA binding activity
increased only after high doses of IR (>1200 cGy). Disruption of p53
responses in U1-Mel cells by E6 transfection also abrogated
G0/G1 cell cycle checkpoint arrest responses
and increased polyploidy after IR, but did not alter radiosensitivity.
These data suggest that abrogation of individual components of this
coordinate IR-activated transcription factor response may lead to
divergent alterations in cell cycle checkpoints, genomic instability,
apoptosis, and survival. Such coordinate transcription factor
activation in human cancer cells is reminiscent of prokaryotic SOS
responses, and further elucidation of these events should shed light on
the initial molecular events in the chromosome instability
phenotype.—Yang, C.-R., Wilson-Van Patten, C., Planchon, S. M.,
Wuerzberger-Davis, S. M., Davis, T. W., Cuthill, C.,
Miyamoto, S., Boothman, D. A. Coordinate modulation of Sp1,
NF-kappa B, and p53 in confluent human malignant melanoma cells after
ionizing radiation.
Key Words: PLDR • Sp1 • retinoblastoma control proteins • NF-B • p53 • ionizing radiation • genomic instability • aneuploid/polyploid • apoptosis
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