Rapid induction of cAMP/PKA pathway during retinoic acid-induced acute promyelocytic leukemia cell differentiation

Zhao, Qiwu; Jiang, Tao; Zhu, Quing; Pm, Jia; Ax, Dou; X, Li; Cheng, Fufu; Waxman, Samuel; Gq, Chen; Sj, Chen; Lanotte, Michel; Chen, Z; Jh, Tong

doi:10.1038/sj.leu.2403226

Cited by 82 publications

(74 citation statements)

References 32 publications

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“…Retinoids directly alter the activity of various protein kinases, including MAPK and protein kinase C isoforms (24,25). A recent study reported that atRA induced rapid cAMP production and increases protein kinase A (PKA) activity in acute myeloblastic leukemia cells, leading to cell differentiation (26). A synergistic effect between atRA and inhibitors of phosphodiesterase also was observed for myeloid differentiation (27).…”

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confidence: 87%

Retinoic Acid Inhibits HIV-1–Induced Podocyte Proliferation through the cAMP Pathway

He¹,

Lü²,

Fleet³

et al. 2007

Journal of the American Society of Nephrology

102

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HIV-associated nephropathy is characterized by renal podocyte proliferation and dedifferentiation. This study found that all-trans retinoic acid (atRA) reverses the effects of HIV-1 infection in podocytes. Treatment with atRA reduced cell proliferation rate by causing G1 arrest and restored the expression of the differentiation markers (synaptopodin, nephrin, podocin, and WT-1) in HIV-1-infected podocytes. It is interesting that both atRA and 9-cis RA increased intracellular cAMP levels in podocytes. Podocytes expressed most isoforms of retinoic acid receptors (RAR) and retinoid X receptors (RXR) with the exception of RXR␥. RAR␣ antagonists blocked atRA-induced cAMP production and its antiproliferative and prodifferentiation effects on podocytes, suggesting that RAR␣ is required. For determination of the effect of increased intracellular cAMP on HIV-infected podocytes, cells were stimulated with either forskolin or 8-bromo-cAMP. Both compounds inhibited cell proliferation significantly and restored synaptopodin expression in HIV-infected podocytes. The effects of atRA were abolished by Rp-cAMP, an inhibitor of the cAMP/protein kinase A pathway and were enhanced by rolipram, an inhibitor of phosphodiesterase 4, suggesting that the antiproliferative and prodifferentiation effects of atRA on HIV-infected podocytes are cAMP dependent. Furthermore, both atRA and forskolin suppressed HIV-induced mitogen-activated protein kinase 1 and 2 and Stat3 phosphorylation. In vivo, atRA reduced proteinuria, cell proliferation, and glomerulosclerosis in HIV-1-transgenic mice. These findings suggest that atRA reverses the abnormal phenotype in HIV-1-infected podocytes by stimulating RAR␣-mediated intracellular cAMP production. These results demonstrate the mechanism by which atRA reverses the proliferation of podocytes that is induced by HIV-1.

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confidence: 87%

Retinoic Acid Inhibits HIV-1–Induced Podocyte Proliferation through the cAMP Pathway

He¹,

Lü²,

Fleet³

et al. 2007

Journal of the American Society of Nephrology

102

View full text Add to dashboard Cite

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“…The activation of cytoplasmic signaling molecules by retinoids has also been reported as an important pathway for induction of leukemia cell differentiation (25). A recent study reported that all-trans retinoic acid (atRA) induces rapid cyclic AMP (cAMP) production and increased protein kinase A (PKA) activity in acute promyeloblastic leukemia cells, leading to cell differentiation (42). The antiproliferative and prodifferentiation effects of atRA suggested a rationale for studying its effect on podocytes infected with HIV type 1 (HIV-1).…”

mentioning

confidence: 99%

Retinoic Acid Utilizes CREB and USF1 in a Transcriptional Feed-Forward Loop in Order To Stimulate MKP1 Expression in Human Immunodeficiency Virus-Infected Podocytes

Lu¹,

Wang

Feng

et al. 2008

Molecular and Cellular Biology

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Nef-induced podocyte proliferation and dedifferentiation via mitogen-activated protein kinase 1,2 (MAPK1,2) activation plays a role in human immunodeficiency virus (HIV) nephropathy pathogenesis. Alltrans retinoic acid (atRA) reverses the HIV-induced podocyte phenotype by activating cyclic AMP (cAMP)/ protein kinase A (PKA) and inhibiting MAPK1,2. Here we show that atRA, through cAMP and PKA, triggers a feed-forward loop involving CREB and USF1 to induce biphasic stimulation of MKP1. atRA stimulated CREB and USF1 binding to the MKP1 gene promoter, as shown by gel shifting and chromatin immunoprecipitation assays. CREB directly mediated the early phase of atRA-induced MKP1 stimulation; whereas the later phase was mediated by CREB indirectly through induction of USF1. These findings were confirmed by a reporter gene assay using the MKP1 promoter with mutation of CRE or Ebox binding sites. Consistent with these findings, the biological effects of atRA on podocytes were inhibited by silencing either MKP1, CREB, or USF1 with small interfering RNA. atRA also induced CREB phosphorylation and MKP1 expression and reduced MAPK1,2 phosphorylation in kidneys of HIV type 1-infected transgenic mice. We conclude that atRA induces sustained activation of MKP1 to suppress Nef-induced activation of the Src-MAPK1,2 pathway, thus returning the podocyte to a more differentiated state. The mechanism involves a feed-forward loop where activation of one transcription factor (TF) (CREB) leads to induction of a second TF (USF1).

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“…There is also accumulating evidence that beyond activation of classic retinoid-pathways, several other signaling cascades are engaged during RA-dependent cell-differentiation and/or growth inhibition. Such pathways involve Map-kinases (17,(23)(24)(25)(26)(27), src-kinases (28), CrkL and Vav proteins (29)(30)(31), PKCγ (16) and PKA (32). Other signaling events implicated in the generation of retinoid-effects include modulation of histone-acetylation (33), suppression of AP-1 activity (34), and regulation of Stat1-phosphorylation (35).…”

Section: Discussionmentioning

confidence: 99%

Role of the translational repressor 4E-BP1 in the regulation of p21Waf1/Cip1 expression by retinoids

Kannan-Thulasiraman

Dolniak²,

Kaur³

et al. 2008

Biochemical and Biophysical Research Communications

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The mechanisms by which retinoids regulate initiation of mRNA translation for proteins that mediate their biological effects are not known. We have previously shown that all-trans-retinoic acid (ATRA) induces mTOR-mediated activation of the p70 S6 kinase, suggesting the existence of a mechanism by which retinoids may regulate mRNA translation. We now demonstrate that treatment of acute promyelocytic leukemia (APL)-derived NB4 cells with ATRA results in dissociation of the translational repressor 4E-BP1 from the eukaryotic initiation factor eIF4E, and subsequent formation of eIF4G-eIF4E complexes. We also show that siRNA-mediated inhibition of 4E-BP1 expression enhances ATRA-dependent upregulation of p21 Waf1/Cip1 , a protein that plays a key role in the induction of retinoid-dependent responses. Our data also establish that ATRA-or cis-RA-dependent p21 Waf1/Cip1 protein expression is enhanced in mouse embryonic fibroblasts with targeted disruption of the 4e-bp1 gene, in the absence of any effects on the transcriptional regulation of the p21 Waf1/Cip1 gene. Moreover, generation of ATRA-or cis-retinoic acid (cis-RA)-antiproliferative responses is enhanced in 4E-BP1 knockout cells. Altogether, these findings strongly suggest a key regulatory role for the translational repressor 4E-BP1 in the generation of retinoid-dependent functional responses.

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Rapid induction of cAMP/PKA pathway during retinoic acid-induced acute promyelocytic leukemia cell differentiation

Cited by 82 publications

References 32 publications

Retinoic Acid Inhibits HIV-1–Induced Podocyte Proliferation through the cAMP Pathway

Retinoic Acid Inhibits HIV-1–Induced Podocyte Proliferation through the cAMP Pathway

Retinoic Acid Utilizes CREB and USF1 in a Transcriptional Feed-Forward Loop in Order To Stimulate MKP1 Expression in Human Immunodeficiency Virus-Infected Podocytes

Role of the translational repressor 4E-BP1 in the regulation of p21Waf1/Cip1 expression by retinoids

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