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Phosphorylation-deficient Stat1 inhibits retinoic acid-induced differentiation and cell cycle arrest in U-937 monoblasts
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
2000 In: Blood, Vol. 96, no 8, 2870-2878 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2000. Vol. 96, no 8, 2870-2878 p.
Identifiers
URN: urn:nbn:se:uu:diva-89626OAI: oai:DiVA.org:uu-89626DiVA: diva2:161272
Available from: 2002-02-01 Created: 2002-02-01Bibliographically approved
In thesis
1. The Role of Stat1 in Retinoic Acid-induced Myelomonocytic Differentiation of Human Leukemia Cells
Open this publication in new window or tab >>The Role of Stat1 in Retinoic Acid-induced Myelomonocytic Differentiation of Human Leukemia Cells
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

All-trans retinoic acid (ATRA), a biologically active metabolite of vitamin A, is a powerful inducer of terminal differentiation and growth arrest of several myeloid cell lines in vitro. Although the efficacy of ATRA as an anti-cancer drug has been demonstrated by the successful treatment of acute promyelocytic leukemia (APL), knowledge concerning the molecular mechanisms directing ATRA-induced differentiation and cell cycle arrest of myeloid cells is lacking. Our results show, for the first time, that the complex regulation of cell cycle proteins and myeloid-specific transcription factors induced by ATRA relies on functional Stat1. We found that Stat1 is activated by both tyrosine-701 and serine-727 phosphorylation upon ATRA-induced differentiation of the human monoblastic cell line U-937. Expression of phosphorylation deficient mutants of Stat1 (Stat1Y701F or Stat1S727A) inhibited both ATRA-induced differentiation and cell cycle arrest of U-937 cells, pointing to a requirement of active Stat1 in these processes.

Detailed analysis of the molecular mechanism of ATRA-induced cell cycle arrest and differentiation showed that the onset of cell cycle arrest was associated with a decrease in c-Myc and cyclin E levels and upregulation of p27Kip1 and p21WAF1/CIP1. This was followed by a rapid fall in cyclin A and B and a coordinate dephosphorylation of the retinoblastoma protein (pRb). The inhibition of ATRA-induced cell-cycle arrest by constitutive expression of Stat1Y701F or Stat1S727A was associated with impaired regulation of these cyclins and p27Kip1, positioning Stat1 activation upstream of these events. To further understand the process of ATRA-induced differentiation, the regulation of myeloid-specific transcription factors was investigated during ATRA-treatment. Notably, ATRA-induced upregulation of Stat2, ICSBP and C/EBP-ε was selectively impaired in sublines expressing Stat1Y701F or Stat1S727A, suggesting an important function of these factors downstream Stat1. Taken together, the work in this thesis clearly demonstrates that Stat1 plays a key role in ATRA-induced terminal differentiation of myeloid cells, through regulation of cell cycle proteins and myeloid-specific transcription factors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2002. 55 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1117
Keyword
Genetics, Stat1, ATRA, U-937, myeloid, differentiation, cell cycle, growth arrest, Genetik
National Category
Medical Genetics
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-1669 (URN)91-554-5224-8 (ISBN)
Public defence
2002-02-22, Rudbecksalen, Rudbeck Laboratory, Uppsala, 09:15
Opponent
Available from: 2002-02-01 Created: 2002-02-01Bibliographically approved

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