Primate-specific RFPL1 gene controls cell-cycle progression through cyclin B1/Cdc2 degradation.
Ret finger protein-like 1 (RFPL1) is a primate-specific target gene of Pax6, a key transcription factor for pancreas, eye and neocortex development. However, its cellular activity remains elusive. In this article, we report that Pax6-elicited expression of the human (h)RFPL1 gene in HeLa cells can be enhanced by in vivo p53 binding to its promoter and therefore investigated the hypothesis that hRFPL1 regulates cell-cycle progression. Upon expression in these cells, hRFPL1 decreased cell number through a kinase-dependent mechanism as PKC activates and Cdc2 inhibits hRFPL1 activity. hRFPL1 antiproliferative activity led to an increased cell population in G(2)/M phase and specific cyclin B1 and Cdc2 downregulations, which were precluded by a proteasome inhibitor. Specifically, cytoplasm-localized hRFPL1 prevented cyclin B1 and Cdc2 accumulation during interphase. Consequently, cells showed a delayed entry into mitosis and cell-cycle lengthening resulting from a threefold increase in G(2) phase duration. Given previous reports that RFPL1 is expressed during cell differentiation, its impact on cell-cycle lengthening therefore provides novel insights into primate-specific development.
Bonnefont
J
J
Department of Pathology and Immunology, School of Medicine, University of Geneva, Rue Michel-Servet 1, Geneva, Switzerland.
Laforge
T
T
Plastre
O
O
Beck
B
B
Sorce
S
S
Dehay
C
C
Krause
K-H
KH
D000818:Animals; D016203:CDC2 Protein Kinase; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002455:Cell Division; D019926:Cyclin B / Q000378:metabolism*; D056744:Cyclin B1 / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases; D005136:Eye Proteins / Q000378:metabolism; D016195:G2 Phase; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007399:Interphase; D008938:Mitosis; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D011323:Primates / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D002352:Carrier Proteins; D019926:Cyclin B; D056744:Cyclin B1; D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C400217:RFPL1 protein, human; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D011493:Protein Kinase C; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases