4-hydroxynonenal and cell cycle.
Lipid peroxidation is very low in proliferating cells and tumours and it might have a role in the regulation of cell proliferation and differentiation by acting through its products. 4-hydroxynonenal (HNE) has been proposed as a mediator of lipoperoxidation effects. It has been demonstrated that HNE can inhibit cell growth and induce differentiation in different leukemic cell lines. The onset of differentiation, induced by HNE, was accompanied by a reduction of c-myc expression. In HL-60 cells, HNE induced the accumulation of cells in the G0/G1 phase of the cell cycle. Cell cycle progression is regulated by three protein classes, the cyclins, the cyclin-dependent kinases (CDKs), and the CDK inhibitors (CKIs). In HL-60 cells, HNE decreased the expression of cyclin D1, D2 and A and caused an increase of p21 (the most important CKI) expression, whereas it did not affect CDK expressions. Since cyclins D/CDK2 and cyclin A/CDK2 phosphorylate pRB, HNE caused an increase of hypophosphorylated pRb. Hypophosphorylated pRb binds and inactivates the E2F transcription factors. Band-shift experiments demonstrated that HNE caused a decrease of "free" E2F, as well as an increase of pRb (and pRB family members) bound to E2F with consequent repression of the transcription.
Barrera
Giuseppina
G
Department of Experimental Medicine and Oncology, University of Turin, Torino, Italy.
Pizzimenti
Stefania
S
Laurora
Stefano
S
Briatore
Federica
F
Toaldo
Cristina
C
Dianzani
Mario Umberto
MU
D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics; D016213:Cyclins / Q000187:drug effects / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D016259:Genes, myc / Q000187:drug effects; D018922:HL-60 Cells / Q000166:cytology; D006801:Humans; D015227:Lipid Peroxidation
D000447:Aldehydes; D016213:Cyclins; D018844:Cyclin-Dependent Kinases; C027576:4-hydroxy-2-nonenal