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The Role of Stat1 in Retinoic Acid-induced Myelomonocytic Differentiation of Human Leukemia Cells
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
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. , p. 55
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1117
Keywords [en]
Genetics, Stat1, ATRA, U-937, myeloid, differentiation, cell cycle, growth arrest
Keywords [sv]
Genetik
National Category
Medical Genetics
Research subject
Pathology
Identifiers
URN: urn:nbn:se:uu:diva-1669ISBN: 91-554-5224-8 (print)OAI: oai:DiVA.org:uu-1669DiVA, id: diva2:161276
Public defence
2002-02-22, Rudbecksalen, Rudbeck Laboratory, Uppsala, 09:15
Opponent
Available from: 2002-02-01 Created: 2002-02-01 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Phosphorylation-deficient Stat1 inhibits retinoic acid-induced differentiation and cell cycle arrest in U-937 monoblasts
Open this publication in new window or tab >>Phosphorylation-deficient Stat1 inhibits retinoic acid-induced differentiation and cell cycle arrest in U-937 monoblasts
2000 In: Blood, Vol. 96, no 8, p. 2870-2878Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-89626 (URN)
Available from: 2002-02-01 Created: 2002-02-01Bibliographically approved
2. Retinoic acid-induced cell cycle arrest of human myeloid cell lines is associated with sequential down-regulation of c-Myc and cyclin E and post-transcriptional upregulation of p27Kip1
Open this publication in new window or tab >>Retinoic acid-induced cell cycle arrest of human myeloid cell lines is associated with sequential down-regulation of c-Myc and cyclin E and post-transcriptional upregulation of p27Kip1
Show others...
2002 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 99, no 6, p. 2199-2206Article in journal (Refereed) Published
Abstract [en]

All-trans retinoic acid (ATRA) is a potential therapeutic agent for the treatment of hematopoietic malignancies, because of its function as an inducer of terminal differentiation of leukemic blasts. Although the efficacy of ATRA as an anticancer drug has been demonstrated by the successful treatment of acute promyelocytic leukemia (APL), the molecular mechanisms of ATRA-induced cell cycle arrest of myeloid cells have not been fully investigated. In this study, we show that the onset of ATRA-induced G0/G1 arrest of human monoblastic U-937 cells is linked to a sharp down-regulation of c-Myc and cyclin E levels and an increase in p21WAF1/CIP1 expression. This is followed by an increase in p27Kip1 protein expression due to enhanced protein stability. The importance of an early decrease in Myc expression for these events was demonstrated by the failure of a U-937 subline with constitutive exogenous expression of v-Myc to cell cycle arrest and regulate cyclin E and p27Kip1 in response to ATRA. Preceding the initiation of G1 arrest, a transient rise in retinoblastoma protein (pRb), p107, and cyclin A levels was detected. Later, a rapid fall in the levels of cyclins A and B and a coordinate dephosphorylation of pRb at Ser780, Ser795, and Ser807/811 coincided with the accumulation of cells in G1. These results thus identify a decrease in c-Myc and cyclin E levels and a posttranscriptional up-regulation of p27Kip1 as important early changes, and position them in the complex chain of events regulating ATRA-induced cell cycle arrest of myeloid cells.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-89627 (URN)10.1182/blood.V99.6.2199 (DOI)
Available from: 2002-02-01 Created: 2002-02-01 Last updated: 2017-12-14Bibliographically approved
3. Serine-727 phosphorylated Stat1 is required for ATRA-induced G0/G1 arrest and the associated regulation of cyclins and p27Kip1
Open this publication in new window or tab >>Serine-727 phosphorylated Stat1 is required for ATRA-induced G0/G1 arrest and the associated regulation of cyclins and p27Kip1
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-89628 (URN)
Available from: 2002-02-01 Created: 2002-02-01Bibliographically approved
4. Inhibition of retinoic acid-induced differentiation of human monoblastic U-937 cells by phosphorylation deficient Stat1 is associated with impaired expression of Stat2, ICSBP and C/EBP-ε
Open this publication in new window or tab >>Inhibition of retinoic acid-induced differentiation of human monoblastic U-937 cells by phosphorylation deficient Stat1 is associated with impaired expression of Stat2, ICSBP and C/EBP-ε
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-89629 (URN)
Available from: 2002-02-01 Created: 2002-02-01 Last updated: 2010-01-13Bibliographically approved

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