Affiliations: Department of Experimental Medicine and Oncology,
University of Turin, Torino, Italy
Note: [] Address for correspondence: Professor Mario Umberto Dianzani,
Dipartimento di Medicina e Oncologia Sperimentale Sezione di Patologia
Generale, Corso Raffaello 30, 10125 Torino, Italy. Tel.: +39 011 6707752; Fax:
+39 011 6707753; E-mail: [email protected]
Abstract: 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.
