Sustained activation of protein kinase C is essential to HL-60 cell differentiation to macrophage.

Aihara, Hiroaki; Asaoka, Yoshinori; Yoshida, Kohsuke; Nishizuka, Yasutomi

doi:10.1073/pnas.88.24.11062

Cited by 114 publications

(67 citation statements)

References 18 publications

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“…HL-60 cells contain PKC-a, PKC-0 and PKC-6, but not PKC-y (Aihara et al, 1991;Edashige et al, 1992). Although many agents are known to block PKC activity, only few are highly specific and none of them exclusively inhibit a given PKCisoform.…”

Section: Discussionmentioning

confidence: 99%

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Up-regulation of p21WAF1 expression in myeloid cells is activated by the protein kinase C pathway

Schwaller

Peters²,

Pabst³

et al. 1997

Br J Cancer

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Summary Phorbol-12-myristate-13-acetate (PMA) induces p21 WAF-1 expression in human myeloid leukaemic HL-60 cells. We show that this induction is specifically mediated by protein kinase C (PKC). In addition, the PKC inhibitor Ro 31-8220 with predominant PKC-a isoform specificity almost completely inhibited PMA-induced up-regulation of p21 WAFi in HL-60 cells as well as in the myelomonocytic leukaemic U937 cells. Pretreatment of HL-60 cells with Ro 31-8220 also inhibited PMA-induced activation of c-raf-1, a known PKC a target. In the phorbol ester-tolerant HL-60 subline (PET) with PKC-P isoform deficiency PMA or bryostatin-1 induced p21 WAFI expression, but to a lesser extent than in wild-type HL-60 cells. In PET cells, Ro 31-8220 also inhibited PMA and bryostatin-1 -induced up-regulation of p21 WAFi expression. Our findings indicate that at least in HL-60 cells up-regulation of p21 WAF-1 is specifically activated by PKC. We suggest that PKC isoforms other than 1B, presumably the PKC-a isoform, are involved in this process.Cancer is characterized by profound alterations both in cell cycle control and in cellular differentiation. Such mechanisms can be studied with the help of cell line models, for example leukaemic cell lines in which both proliferation and differentiation programmes may be analysed. Phorbol ester-induced differentiation of human leukaemic myeloid HL-60 cells towards monocytelike cells is associated with growth arrest in the G, phase of the cell cycle. The CKI p21WAFJ (wild-type p53-activatedftagment-1) is a mediator of G1 cycle arrest induced by wild-type p53 protein (El-Deiry et al, 1993), and in human leukaemia p21WAFI expression may be up-regulated independently from p53 (Schwaller et al, 1995;Zhang et al, 1995;Blagosklonny et al, 1996).Phorbol esters are potent activators of protein kinase C (PKC), a family of serine-threonine protein kinases that act as a central mediators of signal transduction pathways (Castagna, 1987). In HL-60 cells concordant expression pattern of PKC-a and -0 isoenzymes is seen during phorbol ester-induced monocytic differentiation (Aihara et al, 1991;Edashige et al, 1992). To examine the role of PKC in up-regulating p21WAFJ expression, we modulated p21WAFI expression by several PKC activators and inhibitors. We also investigated the expression of c-raf-1, a protein serine-threonine kinase required for p21WAFI induction and up-stream regulation of mitogenactivated protein (MAP) kinase (Blagosklonny et al, 1995).

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Section: Discussionmentioning

confidence: 99%

“…In HL-60 cells concordant expression pattern of PKC-a and -0 isoenzymes is seen during phorbol ester-induced monocytic differentiation (Aihara et al, 1991;Edashige et al, 1992). To examine the role of PKC in up-regulating p21WAFJ expression, we modulated p21WAFI expression by several PKC activators and inhibitors.…”

mentioning

confidence: 99%

Up-regulation of p21WAF1 expression in myeloid cells is activated by the protein kinase C pathway

Schwaller

Peters²,

Pabst³

et al. 1997

Br J Cancer

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“…The only marker tested whose expression was altered by PDE1B2 knockdown was the integrin CD11b (MAC-1). CD11b expression is very low on undifferentiated cells, but its expression is highly induced with PMA treatment (34,35). PDE1B2 shRNA cells up-regulate CD11b to a greater degree than scrambled shRNA cells.…”

Section: Pde1b2 Is Not Required For Differentiation But Affects the Fmentioning

confidence: 99%

PDE1B2 regulates cGMP and a subset of the phenotypic characteristics acquired upon macrophage differentiation from a monocyte

Bender

Beavo

2006

Proc. Natl. Acad. Sci. U.S.A.

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Monocyte-to-macrophage differentiation with the cytokine granulocyte-macrophage colony-stimulating factor induces expression of the cyclic nucleotide phosphodiesterase PDE1B2. However, what role PDE1B2 plays in macrophage biology has not been elucidated. We have addressed this question by inhibiting PDE1B2 induction by using RNA interference. Using a retrovirus-based system, we created HL-60 stable cell lines that express a short-hairpin RNA targeting PDE1B2. HL-60 cells treated with phorbol-12-myristate-13-acetate differentiate to a macrophage-like phenotype and upregulate PDE1B2. However, expression of PDE1B2 short hairpin RNA effectively suppresses PDE1B2 mRNA, protein, and activity up-regulation. Using the HL-60 PDE1B2 knockdown cells and agonists for either adenylyl or guanylyl cyclase, it was found that PDE1B2 predominantly regulates cGMP and plays a lesser role in cAMP regulation in response to cyclase agonists. Furthermore, in intact HL-60 cells, PDE1B2 activity can be regulated by changes in Ca ؉2 levels. Inhibiting PDE1B2 up-regulation does not prevent HL-60 cell differentiation, because several markers of macrophage differentiation are unaffected. However, suppression of PDE1B2 expression alters some aspects of the macrophage-like phenotype, because cell spreading, phagocytic ability, and CD11b expression are augmented. The cAMP analog 8-Bromo-cAMP reverses the changes caused by PDE1B2 knockdown. Also, PDE1B2 knockdown cells have lower basal levels of cAMP and alterations in the phosphorylation state of several probable PKA substrate proteins. Thus, the effects of PDE1B2 on differentiation may ultimately be mediated through decreased cAMP. In conclusion, PDE1B2 regulates a subset of phenotypic changes that occur upon phorbol-12-myristate-13-acetate-induced differentiation and likely also plays a role in differentiated macrophages by regulating agonist-stimulated cGMP levels.cyclic AMP ͉ cyclic GMP ͉ phosphodiesterase

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“…PKC is also the cellular receptor for phorbol esters and other tumor promoters that can substitute for diacylglycerol and directly activate the enzyme (5,6). Phorbol esters elicit a variety of physiological responses in different target cells, including modulation of ion fluxes, secretory responses, changes in gene expression, and inhibition of growth (7)(8)(9)(10)(11)(12).…”

Section: Pkcmentioning

confidence: 99%

A p53-independent G1 Cell Cycle Checkpoint Induced by the Suppression of Protein Kinase C α and θ Isoforms

Deeds

Teodorescu

Chu

et al. 2003

Journal of Biological Chemistry

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The protein kinase C (PKC) family consists of multiple isoforms that are involved in the regulation of diverse cellular responses. Suppression of PKC induces growth arrest in various types of cells. However, the underlying molecular mechanisms have not been thoroughly investigated. In this report, we demonstrated that the concurrent inhibition, rather than separate inhibition, of phorbol ester-dependent PKC ␣ and isoforms is crucial for the induction of G 1 cell cycle arrest and that this negative cell cycle regulation is via p53-independent mechanisms. PKC suppression-mediated growth arrest is associated with the induction of cell cycle inhibitor p21 WAF1/ CIP1 and the occurrence of hypophosphorylated Rb. The G 1 checkpoint induced by the suppression of PKC occurs not only in murine Swiss3T3 but also in p53-deficient cells and human lung cancer cells containing mutated p53. Luciferase and nuclear run-off assays demonstrated that p21 WAF1/CIP1 is, in part, transcriptionally regulated in response to the suppression of PKC ␣ and . However, the stability of p21 mRNA is also augmented after the addition of PKC ␣ and antisense oligonucleotides, indicating the involvement of posttranscriptional mechanisms in p21 WAF1/CIP1 expression. These data suggest the existence of a cell cycle checkpoint pathway regulated by PKC ␣ and isoforms. Furthermore, our findings support the notion that G 1 checkpoint control can be restored in tumor cells containing abnormal p53, by targeting the PKC-regulated p21 WAF1/CIP1 induction.

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Sustained activation of protein kinase C is essential to HL-60 cell differentiation to macrophage.

Cited by 114 publications

References 18 publications

Up-regulation of p21WAF1 expression in myeloid cells is activated by the protein kinase C pathway

Up-regulation of p21WAF1 expression in myeloid cells is activated by the protein kinase C pathway

PDE1B2 regulates cGMP and a subset of the phenotypic characteristics acquired upon macrophage differentiation from a monocyte

A p53-independent G1 Cell Cycle Checkpoint Induced by the Suppression of Protein Kinase C α and θ Isoforms

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