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MYC accelerates p21 CIP ‐induced megakaryocytic differentiation involving early mitosis arrest in leukemia cells
Author(s) -
MuñozAlonso María J.,
Ceballos Laura,
Bretones Gabriel,
Frade Pilar,
León Javier,
Gandarillas Alberto
Publication year - 2012
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22935
Subject(s) - biology , microbiology and biotechnology , mitosis , cellular differentiation , endoreduplication , cell cycle , cell growth , cell , biochemistry , gene
p21 CIP is a potent cell cycle inhibitor often up‐regulated in differentiation. Protooncogene MYC induces cell growth and proliferation, inhibits differentiation and represses p21 CIP . However, both molecules are involved in processes of polyploidisation, cell size increase, differentiation and senescence. It is unclear why MYC has a dual role in differentiation. We have previously shown that overexpression of p21 CIP in K562 myeloid cells induces megakaryocytic differentiation with polyploidy. We have now investigated the requirements for p21 CIP to block mitosis and induce differentiation in the presence of overactivated MYC. Silencing and over‐expression studies showed that p21 CIP is required to induce differentiation. However, the expression of p21 CIP needs to be transient to irreversibly inhibit mitosis but not DNA replication, what leads to polyploidy. Transient overexpression of p21 CIP caused early down‐regulation of mitotic Cyclins and up‐regulation of G1/S Cyclins D and E, changes typical of endoreplication. Interestingly, over‐activation of MYC did not release the proliferative block imposed by p21 CIP and instead, accelerated cell size increase, megakaryocytic differentiation and polyploidisation. Our data suggests that in some systems p21 CIP takes part in a mitosis control driving MYC‐induced cellular growth into differentiation. J. Cell. Physiol. 227: 2069–2078, 2012. © 2011 Wiley Periodicals, Inc.