Revhrshd course of phorbol ester-induced human MYF.Loblastic MI,-I cell terminal differentiation by suppression of RB phosphatases

B. Xu, Brenda Anne Wilson, L. Lu

Research output: Contribution to journalArticlepeer-review

Abstract

Retinoblastoma (RB) gene encodes a nuclear phosphoprotein (pRB) which has been shown to be a key regulator of eukaryotic cell growth. Recent studies strongly suggest an important role for pRB in oncogenic development of the hematopoietic system In the present study, we found that blockade of pRB dephosphorylation reversed the course of TP A-mduced human myeloblastic leukemia cell differentiation to macrophage. The possible mechanism underlying TPA-induced ML-1 cell terminal differentiation was explored using cell and molecular biology approaches. Wlule no significant change m pRB gene expression was found during TPA-induced ML-1 cell differentiation, there was an increase in the amount of the hypophosphorylated form of pRB associated with cell differentiation. Furthermore, the TPAindiioxt differentiation can be blocked by 50-100 μM okadaic acid, an inhibitor of type 1 and 2A protein phosphalase (PP1 & PP2A) The blockade is shown to be correlated with prevention of dephosphorylation of pRB in cells and bypassing of the G, arrest in the cell cycle. Fuither experiments demonstrated that induction of p27, a Ci, cyclin-dependent kinase (CDK) inhibitor, bv increase of intracellular cAMP caused accumulation of dephosphorylated pRB and subsequently resulted in cells arresting in G, phase. The cell differentiation marker, CD14, was not found in the cells arrested mO, phase by cAMP stimulation Taken together, these results suggest that regulation of pRli function is primary and essential ai the postiranslational level in TPA-induced ML-1 coll differentiation. The mechanism of TPA action may act through enhancement of phosphatase pathways rather than impairment CDK pathways. PP 1 is pRibably the primary protein phosphatase regulating pRB function in ML-1 cells. The prieesc effect of TPA en pRB phosphatase functions remains to be investigated.

Original languageEnglish (US)
JournalFASEB Journal
Volume10
Issue number3
StatePublished - Dec 1 1996
Externally publishedYes

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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