Cyclin D1 is up-regulated in hepatocytes in vivo following cell-cycle block induced by retrorsine.
OBJECTIVE
We reported massive liver repopulation by transplanted hepatocytes in rats given retrorsine (RS), a pyrrolizidine alkaloid which blocks proliferation of resident cells. In these studies, molecular alterations induced by RS on hepatocyte cell cycle were investigated.


METHODS
Animals were treated according to the protocol for liver repopulation, i.e. two injections of RS (30 mg/kg) followed by two-thirds partial hepatectomy (PH) and were sacrificed at various time points thereafter. Livers were analyzed for the expression of cell cycle-related genes.


RESULTS
Prior to PH, increased cyclin D1 mRNA and protein levels were found in livers of RS-treated rats. Expression of PCNA was also increased; however, DNA synthesis was not significantly changed. Other cyclins, including cyclin B and cyclin E, were not induced. Cyclin D1 expression increased in controls post-PH and then declined by 48 h, as expected. By contrast, no such modulation of cyclin D1 levels was seen in RS group receiving PH and expression remained high at 48 h, without mitotic division.


CONCLUSIONS
Exposure to RS is able to block cell cycle progression after cyclin D1 and PCNA induction, but prior to S phase. Such persistent block outside the resting phase may contribute to the selective replacement of resident cells during liver repopulation.
Pitzalis
Sabrina
S
Section of Experimental Pathology, Department of Biomedical Sciences and Biotechnology, University of Cagliari, Via Porcell, 4, 09125 Cagliari, Italy.
Doratiotto
Silvia
S
Greco
Marianna
M
Montisci
Stefania
S
Pasciu
Daniela
D
Porcu
Giovanna
G
Pani
Paolo
P
Laconi
Sergio
S
Laconi
Ezio
E
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001483:Base Sequence; D002453:Cell Cycle / Q000187:drug effects*; D019926:Cyclin B / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics*; D017931:DNA Primers; D004261:DNA Replication / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology*; D008297:Male; D014176:Protein Biosynthesis; D011763:Pyrrolizidine Alkaloids / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D014158:Transcription, Genetic
D000972:Antineoplastic Agents, Phytogenic; D019926:Cyclin B; D017931:DNA Primers; D011763:Pyrrolizidine Alkaloids; D012333:RNA, Messenger; D019938:Cyclin D1; C003300:retrorsine