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MAD1 and p27(KIP1) cooperate to promote terminal differentiation of granulocytes and to inhibit Myc expression and cyclin E-CDK2 activity.

McArthur, Grant A and Foley, Kevin P and Fero, Matthew L and Walkley, Carl R and Deans, Andrew J and Roberts, James M and Eisenman, Robert N (2002) MAD1 and p27(KIP1) cooperate to promote terminal differentiation of granulocytes and to inhibit Myc expression and cyclin E-CDK2 activity. Molecular and cellular biology, 22 (9). pp. 3014-3023. ISSN 0270-7306

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To understand how cellular differentiation is coupled to withdrawal from the cell cycle, we have focused on two negative regulators of the cell cycle, the MYC antagonist MAD1 and the cyclin-dependent kinase inhibitor p27(KIP1). Generation of Mad1/p27(KIP1) double-null mice revealed a number of synthetic effects between the null alleles of Mad1 and p27(KIP1), including embryonic lethality, increased proliferation, and impaired differentiation of granulocyte precursors. Furthermore, with granulocyte cell lines derived from the Mad1/p27(KIP1) double-null mice, we observed constitutive Myc expression and cyclin E-CDK2 kinase activity as well as impaired differentiation following treatment with an inducer of differentiation. By contrast, similar treatment of granulocytes from Mad1 or p27(KIP1) single-null mice resulted in differentiation accompanied by downregulation of both Myc expression and cyclin E-CDK2 kinase activity. In the double-null granulocytic cells, addition of a CDK2 inhibitor in the presence of differentiation inducer was sufficient to restore differentiation and reduce Myc levels. We conclude that Mad1 and p27(KIP1) operate, at least in part, by distinct mechanisms to downregulate CDK2 activity and Myc expression in order to promote cell cycle exit during differentiation.

Item Type: Article
Additional Information: This article is freely available in PubMed Central and at the journal's website.
DOI: 10.1128/MCB.22.9.3014-3023.2002
PubMed ID: 11940659
PMCID: PMC133749
Grant Numbers: DRG-076, RO1CA57138, HL54881
Keywords or MeSH Headings: Animals; CDC2-CDC28 Kinases; Cell Cycle/drug effects; Cell Cycle Proteins/metabolism; Cell Differentiation; Cell Line; Cyclin E/antagonists & inhibitors/metabolism; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinases/antagonists & inhibitors/metabolism; Fatty Acids, Unsaturated/pharmacology; Female; Flow Cytometry; Gene Expression Regulation, Neoplastic; Genes, myc/genetics; Granulocytes/cytology/metabolism; Hematopoietic Stem Cells/metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclear Proteins; Phosphoproteins/metabolism; Protein-Serine-Threonine Kinases/antagonists & inhibitors/metabolism; RNA, Messenger/metabolism; Repressor Proteins/metabolism; Retinoblastoma Protein/metabolism; Tetrahydronaphthalenes/pharmacology; Time Factors; Tumor Suppressor Proteins/metabolism;
Subjects: Molecules > Genes > Oncogenes
Cellular and Organismal Processes > Cell Physiology > Cell cycle
Molecules > Proteins > Cell cycle proteins
Cellular and Organismal Processes > Cell Physiology > Cell differentiation
Depositing User: Library Staff
Date Deposited: 24 Nov 2008 22:55
Last Modified: 07 May 2010 21:41

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