4-Hydroxynonenal modulation of p53 family gene expression in the SK-N-BE neuroblastoma cell line.
4-Hydroxynonenal (HNE), a product of lipid peroxidation, inhibits proliferation of several tumor cells. The p53 tumor suppressor protein plays a critical role in cell cycle control, by inducing p21 expression, and in apoptosis, by inducing bax expression. Recently, two other proteins with many p53-like properties, TAp73 (p73) and TAp63 (p63), have been discovered. SK-N-BE human neuroblastoma cells express the three p53 family proteins and can be used for the study of their induction. We investigated HNE action in the control of proliferation, differentiation, and apoptosis in SK-N-BE cells and the HNE effect on the expression of p53, p63, p73, p21, bax, and G1 cyclins. Retinoic acid (RA) was used as a positive control. HNE inhibited cell proliferation without inducing differentiation; it decreased S-phase cells and increased the number of apoptotic cells. RA reduced the proportion of S-phase cells and did not induce apoptosis. HNE increased p53, p73, p63, p21, and bax expression at different time points. HNE reduced cyclin D2 expression and the phosphorylation of pRb protein. Our results demonstrated that HNE inhibits SK-N-BE cell proliferation by increasing the expression of p53 family proteins and p53 target proteins which modulate cell cycle progression and apoptosis.
Laurora
Stefano
S
Department of Experimental Medicine and Oncology, Section of General Pathology, University of Turin, Corso Raffaello 30, 10125 Turin, Italy.
Tamagno
Elena
E
Briatore
Federica
F
Bardini
Paola
P
Pizzimenti
Stefania
S
Toaldo
Cristina
C
Reffo
Patrizia
P
Costelli
Paola
P
Dianzani
Mario U
MU
Danni
Oliviero
O
Barrera
Giuseppina
G
D000447:Aldehydes / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002851:Chromatography, High Pressure Liquid; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005434:Flow Cytometry; D016147:Genes, Tumor Suppressor; D018922:HL-60 Cells; D006801:Humans; D050356:Lipid Metabolism; D008856:Microscopy, Fluorescence; D009447:Neuroblastoma / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D010545:Peroxides / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D014212:Tretinoin / Q000378:metabolism; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein
D000447:Aldehydes; C494826:BAX protein, human; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010545:Peroxides; D010750:Phosphoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein; C115051:TP63 protein, human; C000606460:TP73 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D014212:Tretinoin; C027576:4-hydroxy-2-nonenal