The Role of Stat1 in Retinoic Acid-induced Myelomonocytic Differentiation of Human Leukemia Cells [Elektronisk resurs]
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Dimberg, Anna, 1971- (författare)
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Touw, Ivo (opponent)
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Uppsala universitet Medicinska vetenskapsområdet (utgivare)
- Publicerad: Uppsala : Acta Universitatis Upsaliensis, 2002
- Engelska 55
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Serie: Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 0282-7476 0282-7476 ; 1117
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Sammanfattning
Ämnesord
Stäng
- 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 p27 Kip1 and p21 WAF1/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 p27 Kip1 , 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.
Ämnesord
- Medical and Health Sciences (hsv)
- Basic Medicine (hsv)
- Medical Genetics (hsv)
- Medicin och hälsovetenskap (hsv)
- Medicinska och farmaceutiska grundvetenskaper (hsv)
- Medicinsk genetik (hsv)
- MEDICINE (svep)
- Dermatology and venerology,clinical genetics, internal medicine (svep)
- Clinical genetics (svep)
- MEDICIN (svep)
- Dermatologi och venerologi, klinisk genetik, invärtesmedicin (svep)
- Klinisk genetik (svep)
- Pathology (uu)
- patologi (uu)
Genre
- government publication (marcgt)
Indexterm och SAB-rubrik
- Genetics
- Stat1
- ATRA
- U-937
- myeloid
- differentiation
- cell cycle
- growth arrest
- Genetik
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