Side-chain modified vitamin D analogs require activation of both PI 3-K and erk1,2 signal transduction pathways to induce differentiation of human promyelocytic leukemia cells

• Autorzy: Marcinkowska E. , Kutner A.
• Języki publikacji: EN

Abstrakty

EN

Synthetic analogs of vitamin D for potential use in differentiation therapy should se­lectively regulate genes necessary for differentiation without inducing any perturba­tions in calcium homeostasis. PRI-1906, an analog of vitamin D2, and PRI-2191, an analog of vitamin D3 bind nuclear vitamin D receptor (nVDR) with substantially lower affinity than 1,25-dihydroxyvitamin D3 (1,25-D3), but have higher differentiation-in­ducing activity as estimated in HL-60 leukemia cell model. To examine how their in­creased differentiation-inducing activity is regulated we tested the hypothesis that membrane-mediated events, unrelated to nVDR, take part in the differentiation in re­sponse to PRI-1906 and PRI-2191. The induction of leukemia cell differentiation in response to the analogs of vitamin D was inhibited by LY294002 (phosphatidyl- inositol 3-kinase inhibitor), PD98059 (inhibitor of MEK1,2, an upstream regulator of extracellular-signal regulated kinase) and rapamycin (p70 S6K inhibitor) pointing out that activation of signal transduction pathways unrelated to nVDR is necessary for differentiation. On the other hand, inhibition of cytosolic phospholipase A2 acceler­ated the differentiation of HL-60 cells induced by either 1,25-D3 or by the vitamin D analogs suggesting possible existence of a feedback loop between extracellular-signal regulated kinases and phospholipase A2.

Słowa kluczowe

EN

calcium homeostasis; vitamin D3; cell; synthetic analogue; leukemic cell; signal transduction; vitamin D; 1,25-dihydroxyvitamin D3; vitamin D2; man; nuclear vitamin D; therapy; promyelocytic leukemia; differentiation; HL-60 cell; phosphatidylinositol 3-kinase

• Wydawca: -
• Czasopismo: Acta Biochimica Polonica
• Rocznik: 2002
• Tom: 49
• Numer: 2
• Opis fizyczny: p.393-406,fig.

Twórcy

autor

Marcinkowska E.

• Polish Academy of Sciences, R.Weigla 12, 53-114 Wroclaw, Poland

autor

Kutner A.

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