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Role of cell cycle regulatory molecules in retinoic acid‐ and vitamin D3‐induced differentiation of acute myeloid leukaemia cells
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| Zeitschriftentitel: | Cell Proliferation |
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| Personen und Körperschaften: | , |
| In: | Cell Proliferation, 47, 2014, 3, S. 200-210 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Wiley
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| Schlagwörter: |
| Zusammenfassung: | <jats:title>Abstract</jats:title><jats:p>The important role of cell cycle regulatory molecules in all trans‐retinoic acid (<jats:styled-content style="fixed-case">ATRA</jats:styled-content>)‐ and vitamin D3‐induced growth inhibition and differentiation induction has been intensively studied in both acute myeloid leukaemia primary cells and a variety of leukaemia cell lines. Cyclin‐dependent kinases (<jats:styled-content style="fixed-case">CDK</jats:styled-content>)‐activating kinase has been demonstrated to interact with retinoic acid receptor (<jats:styled-content style="fixed-case">RAR</jats:styled-content>)α in acute promyelocytic leukaemia cells, and inhibition of <jats:styled-content style="fixed-case">CDK</jats:styled-content>‐activating kinase by <jats:styled-content style="fixed-case">ATRA</jats:styled-content> causes hypophosphorylation of PML‐RARα, leading to myeloid differentiation. In many cases, downregulation of <jats:styled-content style="fixed-case">CDK</jats:styled-content> activity by <jats:styled-content style="fixed-case">ATRA</jats:styled-content> and vitamin D3 is a result of elevated p21‐ and p27‐bound <jats:styled-content style="fixed-case">CDK</jats:styled-content>s. Activation of p21 is regulated at the transcriptional level, whereas elevated p27 results from both (indirectly) transcriptional activation and post‐translational modifications. <jats:styled-content style="fixed-case">CDK</jats:styled-content> inhibitors (<jats:styled-content style="fixed-case">CKI</jats:styled-content>s) of the <jats:styled-content style="fixed-case">INK</jats:styled-content> family, such as p15, p16 and p18, are mainly involved in inhibition of cell proliferation, whereas CIP/KIP members, such as p21, regulate both growth arrest and induction of differentiation. <jats:styled-content style="fixed-case">ATRA</jats:styled-content> and vitamin D3 can also downregulate expression of G1 <jats:styled-content style="fixed-case">CDK</jats:styled-content>s, especially <jats:styled-content style="fixed-case">CDK</jats:styled-content>2 and <jats:styled-content style="fixed-case">CDK</jats:styled-content>6. Inhibition of cyclin E expression has only been observed in <jats:styled-content style="fixed-case">ATRA</jats:styled-content>‐ but not in vitamin D3‐treated leukaemic cells. <jats:italic>In vitro,</jats:italic> not only dephosphorylation of pRb but also elevation of total pRb is required for <jats:styled-content style="fixed-case">ATRA</jats:styled-content> and vitamin D3 to suppress growth and trigger their differentiation. Finally, sharp reduction in c‐Myc has been observed in several leukaemia cell lines treated with <jats:styled-content style="fixed-case">ATRA</jats:styled-content>, which may regulate expression of <jats:styled-content style="fixed-case">CDK</jats:styled-content>s and <jats:styled-content style="fixed-case">CKI</jats:styled-content>s.</jats:p> |
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| Umfang: | 200-210 |
| ISSN: |
0960-7722
1365-2184 |
| DOI: | 10.1111/cpr.12100 |