1,25-Dihydroxyvitamin D3 induces differentiation of a retinoic acid- resistant acute promyelocytic leukemia cell line (UF-1) associated with expression of p21(WAF1/CIP1) and p27(KIP1)

Akihiro Muto, Masahiro Kizaki, Kenji Yamato, Yohko Kawai, Maiko Matsushita, Hironori Ueno, Masahiro Ohguchi, Tatsuji Nishihara, H. Phillip Koeffler, Yasuo Ikeda

Research output: Contribution to journalArticle

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Abstract

Retinoic acid (RA) resistance is a serious problem for patients with acute promyelocytic leukemia (APL) who are receiving all-trans RA. However, the mechanisms and strategies to overcome RA resistance by APL cells are still unclear. The biologic effects of RA are mediated by two distinct families of transcriptional factors: RA receptors (RARs) and retinoid X receptors (RXRs). RXRs heterodimerize with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] receptor (VDR), enabling their efficient transcriptional activation. The cyclin-dependent kinase (cdk) inhibitor p21(WAF1/CIP1) has a vitamin D3-responsive element (VDRE) in its promoter, and 1,25(OH)2D3 enhances the expression of p21(WAF1/CIP1) and induces differentiation of selected myeloid leukemic cell lines. We have recently established a novel APL cell line (UF-1) with features of RA resistance. 1,25(OH)2D3 can induce growth inhibition and G1 arrest of UF-1 cells, resulting in differentiation of these cells toward granulocytes. This 1,25(OH)2D3-induced G1 arrest is enhanced by all-trans RA. Also, 1,25(OH)2D3 (10-10 to 10-7 mol/L) in combination with RA markedly inhibits cellular proliferation in a dose- and time-dependent manner. Associated with these findings, the levels of p21(WAF1/CIP1) and p27(KIP1) mRNA and protein increased in these cells. Northern blot analysis showed that p21(WAF1/CIP1) and p27(KIP1) mRNA and protein increased in these cells. Northern blot analysis showed that p21(WAF1/CIP1) and p27(KIP1) transcripts were induced after 6 hours' exposure to 1,25(OH)2D3 and then decreased to basal levels over 48 hours. Western blot experiments showed that p21(WAF1/CIP1) protein levels increased and became detectable after 12 hours of 1,25(OH)2D3 treatment and induction of p27(KIP1) protein was much more gradual and sustained in UF-1 cells. Interestingly, the combination of 1,25(OH)2D3 and RA markedly enhanced the levels of p27(KIP1) transcript and protein as compared with levels induced by 1,25(OH)2D3 alone. In addition, exogenous p27(KIP1) expression can enhance the level of CD11b antigen in myeloid leukemic cells. In contrast, RA alone can induce G1 arrest of UF-1 cells; however, it did not result in an increase of p21(WAF1/CIP1) and p27(KIP1) transcript and protein expression in RA- resistant cells. Taken together, we conclude that 1,25(OH)2D3 induces increased expression of cdk inhibitors, which mediates a G1 arrest, and this may be associated with differentiation of RA-resistant UF-1 cells toward mature granulocytes.

Original languageEnglish
Pages (from-to)2225-2233
Number of pages9
JournalBlood
Volume93
Issue number7
Publication statusPublished - 1999 Apr 1
Externally publishedYes

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Acute Promyelocytic Leukemia
Calcitriol
Tretinoin
Cells
Cell Line
Acid resistance
Retinoid X Receptors
Proteins
Myeloid Cells
Granulocytes
Northern Blotting
CD11b Antigens
Cyclin-Dependent Kinase Inhibitor p21
Messenger RNA
Retinoic Acid Receptors
Cyclin-Dependent Kinases
Cholecalciferol
Transcriptional Activation
Cell Differentiation
Western Blotting

ASJC Scopus subject areas

  • Hematology

Cite this

1,25-Dihydroxyvitamin D3 induces differentiation of a retinoic acid- resistant acute promyelocytic leukemia cell line (UF-1) associated with expression of p21(WAF1/CIP1) and p27(KIP1). / Muto, Akihiro; Kizaki, Masahiro; Yamato, Kenji; Kawai, Yohko; Matsushita, Maiko; Ueno, Hironori; Ohguchi, Masahiro; Nishihara, Tatsuji; Koeffler, H. Phillip; Ikeda, Yasuo.

In: Blood, Vol. 93, No. 7, 01.04.1999, p. 2225-2233.

Research output: Contribution to journalArticle

Muto, A, Kizaki, M, Yamato, K, Kawai, Y, Matsushita, M, Ueno, H, Ohguchi, M, Nishihara, T, Koeffler, HP & Ikeda, Y 1999, '1,25-Dihydroxyvitamin D3 induces differentiation of a retinoic acid- resistant acute promyelocytic leukemia cell line (UF-1) associated with expression of p21(WAF1/CIP1) and p27(KIP1)', Blood, vol. 93, no. 7, pp. 2225-2233.
Muto, Akihiro ; Kizaki, Masahiro ; Yamato, Kenji ; Kawai, Yohko ; Matsushita, Maiko ; Ueno, Hironori ; Ohguchi, Masahiro ; Nishihara, Tatsuji ; Koeffler, H. Phillip ; Ikeda, Yasuo. / 1,25-Dihydroxyvitamin D3 induces differentiation of a retinoic acid- resistant acute promyelocytic leukemia cell line (UF-1) associated with expression of p21(WAF1/CIP1) and p27(KIP1). In: Blood. 1999 ; Vol. 93, No. 7. pp. 2225-2233.
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abstract = "Retinoic acid (RA) resistance is a serious problem for patients with acute promyelocytic leukemia (APL) who are receiving all-trans RA. However, the mechanisms and strategies to overcome RA resistance by APL cells are still unclear. The biologic effects of RA are mediated by two distinct families of transcriptional factors: RA receptors (RARs) and retinoid X receptors (RXRs). RXRs heterodimerize with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] receptor (VDR), enabling their efficient transcriptional activation. The cyclin-dependent kinase (cdk) inhibitor p21(WAF1/CIP1) has a vitamin D3-responsive element (VDRE) in its promoter, and 1,25(OH)2D3 enhances the expression of p21(WAF1/CIP1) and induces differentiation of selected myeloid leukemic cell lines. We have recently established a novel APL cell line (UF-1) with features of RA resistance. 1,25(OH)2D3 can induce growth inhibition and G1 arrest of UF-1 cells, resulting in differentiation of these cells toward granulocytes. This 1,25(OH)2D3-induced G1 arrest is enhanced by all-trans RA. Also, 1,25(OH)2D3 (10-10 to 10-7 mol/L) in combination with RA markedly inhibits cellular proliferation in a dose- and time-dependent manner. Associated with these findings, the levels of p21(WAF1/CIP1) and p27(KIP1) mRNA and protein increased in these cells. Northern blot analysis showed that p21(WAF1/CIP1) and p27(KIP1) mRNA and protein increased in these cells. Northern blot analysis showed that p21(WAF1/CIP1) and p27(KIP1) transcripts were induced after 6 hours' exposure to 1,25(OH)2D3 and then decreased to basal levels over 48 hours. Western blot experiments showed that p21(WAF1/CIP1) protein levels increased and became detectable after 12 hours of 1,25(OH)2D3 treatment and induction of p27(KIP1) protein was much more gradual and sustained in UF-1 cells. Interestingly, the combination of 1,25(OH)2D3 and RA markedly enhanced the levels of p27(KIP1) transcript and protein as compared with levels induced by 1,25(OH)2D3 alone. In addition, exogenous p27(KIP1) expression can enhance the level of CD11b antigen in myeloid leukemic cells. In contrast, RA alone can induce G1 arrest of UF-1 cells; however, it did not result in an increase of p21(WAF1/CIP1) and p27(KIP1) transcript and protein expression in RA- resistant cells. Taken together, we conclude that 1,25(OH)2D3 induces increased expression of cdk inhibitors, which mediates a G1 arrest, and this may be associated with differentiation of RA-resistant UF-1 cells toward mature granulocytes.",
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T1 - 1,25-Dihydroxyvitamin D3 induces differentiation of a retinoic acid- resistant acute promyelocytic leukemia cell line (UF-1) associated with expression of p21(WAF1/CIP1) and p27(KIP1)

AU - Muto, Akihiro

AU - Kizaki, Masahiro

AU - Yamato, Kenji

AU - Kawai, Yohko

AU - Matsushita, Maiko

AU - Ueno, Hironori

AU - Ohguchi, Masahiro

AU - Nishihara, Tatsuji

AU - Koeffler, H. Phillip

AU - Ikeda, Yasuo

PY - 1999/4/1

Y1 - 1999/4/1

N2 - Retinoic acid (RA) resistance is a serious problem for patients with acute promyelocytic leukemia (APL) who are receiving all-trans RA. However, the mechanisms and strategies to overcome RA resistance by APL cells are still unclear. The biologic effects of RA are mediated by two distinct families of transcriptional factors: RA receptors (RARs) and retinoid X receptors (RXRs). RXRs heterodimerize with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] receptor (VDR), enabling their efficient transcriptional activation. The cyclin-dependent kinase (cdk) inhibitor p21(WAF1/CIP1) has a vitamin D3-responsive element (VDRE) in its promoter, and 1,25(OH)2D3 enhances the expression of p21(WAF1/CIP1) and induces differentiation of selected myeloid leukemic cell lines. We have recently established a novel APL cell line (UF-1) with features of RA resistance. 1,25(OH)2D3 can induce growth inhibition and G1 arrest of UF-1 cells, resulting in differentiation of these cells toward granulocytes. This 1,25(OH)2D3-induced G1 arrest is enhanced by all-trans RA. Also, 1,25(OH)2D3 (10-10 to 10-7 mol/L) in combination with RA markedly inhibits cellular proliferation in a dose- and time-dependent manner. Associated with these findings, the levels of p21(WAF1/CIP1) and p27(KIP1) mRNA and protein increased in these cells. Northern blot analysis showed that p21(WAF1/CIP1) and p27(KIP1) mRNA and protein increased in these cells. Northern blot analysis showed that p21(WAF1/CIP1) and p27(KIP1) transcripts were induced after 6 hours' exposure to 1,25(OH)2D3 and then decreased to basal levels over 48 hours. Western blot experiments showed that p21(WAF1/CIP1) protein levels increased and became detectable after 12 hours of 1,25(OH)2D3 treatment and induction of p27(KIP1) protein was much more gradual and sustained in UF-1 cells. Interestingly, the combination of 1,25(OH)2D3 and RA markedly enhanced the levels of p27(KIP1) transcript and protein as compared with levels induced by 1,25(OH)2D3 alone. In addition, exogenous p27(KIP1) expression can enhance the level of CD11b antigen in myeloid leukemic cells. In contrast, RA alone can induce G1 arrest of UF-1 cells; however, it did not result in an increase of p21(WAF1/CIP1) and p27(KIP1) transcript and protein expression in RA- resistant cells. Taken together, we conclude that 1,25(OH)2D3 induces increased expression of cdk inhibitors, which mediates a G1 arrest, and this may be associated with differentiation of RA-resistant UF-1 cells toward mature granulocytes.

AB - Retinoic acid (RA) resistance is a serious problem for patients with acute promyelocytic leukemia (APL) who are receiving all-trans RA. However, the mechanisms and strategies to overcome RA resistance by APL cells are still unclear. The biologic effects of RA are mediated by two distinct families of transcriptional factors: RA receptors (RARs) and retinoid X receptors (RXRs). RXRs heterodimerize with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] receptor (VDR), enabling their efficient transcriptional activation. The cyclin-dependent kinase (cdk) inhibitor p21(WAF1/CIP1) has a vitamin D3-responsive element (VDRE) in its promoter, and 1,25(OH)2D3 enhances the expression of p21(WAF1/CIP1) and induces differentiation of selected myeloid leukemic cell lines. We have recently established a novel APL cell line (UF-1) with features of RA resistance. 1,25(OH)2D3 can induce growth inhibition and G1 arrest of UF-1 cells, resulting in differentiation of these cells toward granulocytes. This 1,25(OH)2D3-induced G1 arrest is enhanced by all-trans RA. Also, 1,25(OH)2D3 (10-10 to 10-7 mol/L) in combination with RA markedly inhibits cellular proliferation in a dose- and time-dependent manner. Associated with these findings, the levels of p21(WAF1/CIP1) and p27(KIP1) mRNA and protein increased in these cells. Northern blot analysis showed that p21(WAF1/CIP1) and p27(KIP1) mRNA and protein increased in these cells. Northern blot analysis showed that p21(WAF1/CIP1) and p27(KIP1) transcripts were induced after 6 hours' exposure to 1,25(OH)2D3 and then decreased to basal levels over 48 hours. Western blot experiments showed that p21(WAF1/CIP1) protein levels increased and became detectable after 12 hours of 1,25(OH)2D3 treatment and induction of p27(KIP1) protein was much more gradual and sustained in UF-1 cells. Interestingly, the combination of 1,25(OH)2D3 and RA markedly enhanced the levels of p27(KIP1) transcript and protein as compared with levels induced by 1,25(OH)2D3 alone. In addition, exogenous p27(KIP1) expression can enhance the level of CD11b antigen in myeloid leukemic cells. In contrast, RA alone can induce G1 arrest of UF-1 cells; however, it did not result in an increase of p21(WAF1/CIP1) and p27(KIP1) transcript and protein expression in RA- resistant cells. Taken together, we conclude that 1,25(OH)2D3 induces increased expression of cdk inhibitors, which mediates a G1 arrest, and this may be associated with differentiation of RA-resistant UF-1 cells toward mature granulocytes.

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