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A more recent version of this article appeared on November 1, 2002
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Submitted on April 19, 2002
Revised on July 23, 2002
Accepted on August 8, 2002
1 Department of Biochemistry, Instituto de Investigaciones Biomédicas "Alberto Sols", Universidad Autónoma de Madrid- CSIC, Arturo Duperier, 4. 28029 Madrid, Spain
* Corresponding author. E-mail address: ccales{at}iib.uam.es.
Endomitosis is the process by which mammalian megakaryocytes become polyploid during terminal differentiation. As in other endoreplicating cells, cyclin-cdk complexes are distinctly regulated, probably to overcome the strict mechanisms that prevent re-replication in most somatic cells. We have asked whether key factors involved in the assembly and licensing of replication origins are equally regulated during endomitosis. Cdc6, cdt1 and geminin expression was analysed during differentiation of two human megakaryoblastic cell lines, HEL and K562, which respectively do and do not establish endoreplication cycles. Geminin was down-regulated, whereas cdt1 levels were maintained upon differentiation of both cell lines, independently of whether cells entered extra S-phases. In contrast, cdc6 was present and remained nuclear only in differentiated endoreplicating cells. Interestingly, cdc6 protein expression was re-established in K562 cells that underwent endomitosis after transient or stable cyclin E over-expression. The high levels of cyclin E reached in these cells appeared to influence the stabilization of cdc6 protein rather than its RNA transcription rate. Finally, cdc6 overexpression drove HEL cells into endoreplication cycles in the absence of differentiation stimuli. Our results show that both cdt1 and cdc6 are differentially regulated during megakaryocytic differentiation and suggest an active role of cdc6 in endomitosis.
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