Transforming growth factor β-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 up-regulation Journal Article

   

Authors:	Scandura, J. M.; Boccuni, P.; Massagué, J.; Nimer, S. D.
Article Title:	Transforming growth factor β-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 up-regulation
Abstract:	Transforming growth factor β (TGFβ) is one of few known negative regulators of hematopoiesis, yet the mechanisms by which it affects cell cycle arrest and stem cell quiescence are poorly understood. Induction of the cyclin-dependent kinase inhibitors, p15INK4b (p15) and p21WAF1 (p21) is important for TGFβ-mediated cytostasis in epithelial cells but not in hematopoietic cells. Using primary human hematopoietic cells and microarray analysis, we identified p57KIP2 (p57) as the only cyclin-dependent kinase inhibitor induced by TGFβ. Up-regulation of p57 mRNA and protein occurs before TGFβ-induced G1 cell cycle arrest, requires transcription, and is mediated via a highly conserved region of the proximal p57 promoter. The up-regulation of p57 is essential for TGFβ-induced cell cycle arrest in these cells, because two different small interfering RNAs that prevent p57 up-regulation block the cytostatic effects of TGFβ on human hematopoietic cells. Reduction of basal p57 expression by this approach also allows hematopoietic cells to proliferate more readily in the absence of TGFβ. p57 is a putative tumor suppressor gene whose expression is frequently silenced by promoter hypermethylation in hematologic malignancies. Our studies identify a molecular pathway by which TGFβ mediates its cytostatic effects on human hematopoietic cells and suggests an explanation for the frequent silencing of p57 expression.
Keywords:	signal transduction; controlled study; human cell; promoter region; nonhuman; cell proliferation; cells, cultured; cell cycle; gene expression; gene expression profiling; transforming growth factor beta; small interfering rna; cell line, tumor; hela cells; dna methylation; nuclear proteins; tumor suppressor gene; hematologic malignancy; transcription regulation; conserved sequence; messenger rna; rna, messenger; oligonucleotide array sequence analysis; cell transformation; nucleotide sequence; recombinant proteins; hematopoietic cell; hematopoietic stem cells; epithelium cell; hematopoiesis; dna microarray; gene silencing; up-regulation; cyclin dependent kinase inhibitor; protein p21; genomic imprinting; genetic conservation; cell cycle g1 phase; protein isoforms; cytostasis; protein p57; cyclin-dependent kinase inhibitor; promoter regions (genetics); cyclin-dependent kinase inhibitor p57; humans; human; priority journal; article; negative regulators; transcription control; protein p15
Journal Title:	Proceedings of the National Academy of Sciences of the United States of America
Volume:	101
Issue:	42
ISSN:	0027-8424
Publisher:	National Academy of Sciences
Date Published:	2004-10-19
Start Page:	15231
End Page:	15236
Language:	English
DOI:	10.1073/pnas.0406771101
PROVIDER:	scopus
PMCID:	PMC524079
PUBMED:	15477587
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-6344293545&partnerID=40&md5=c337f84b6653bb6c6132b7f02efd90dd
Notes:	Proc. Natl. Acad. Sci. U. S. A. -- Cited By (since 1996):112 -- Export Date: 16 June 2014 -- CODEN: PNASA -- Molecular Sequence Numbers: GENBANK: XM_006479; -- Source: Scopus

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