Summary
Among the three major mitogen-activated protein kinase (MAPK) cascades—the extracellular signal regulated kinase (ERK) pathway, the c-JUN N-terminal/stress-activated protein kinase (JNK/SAPK) pathway, and the reactivating kinase (p38) pathway—retinoic acid selectively utilizes ERK but not JNK/SAPK or p38 when inducing myeloid differentiation of HL-60 human myeloblastic leukemia cells. Retinoic acid is known to active ERK2. The present data show that the activation is selective for this MAPK pathway. JNK/SAPK or p38 are not activated by retinoic acid. Presumably because it activates relevant signaling pathways including MAPK, the polyoma middle T antigen, as well as certain transformation defective mutants thereof, is known to promote retinoic acid-induced differentiation, although the mechanism of action is not well understood. The present results show that consistent with the selective involvement of ERK2, ectopic expression of either the polyoma middle T antigen or its dl23 mutant, which is defective for PLCγ and PI-3 kinase activation, or the Δ205 mutant, which in addition is also weakened for activation of src-like kinases, caused no enhanced JNK/SAPK or p38 kinase activity that promoted the effects of retinoic acid. However, all three of these polyoma antigens are known to enhance ERK2 activation and promote differentiation induced by retinoic acid. Polyoma-activated MAPK signaling relevant to retinoic acid-induced differentiation is thus restricted to ERK2 and does not involve JNK/SAPK or p38. Taken together, the data indicate that among the three parallel MAPK pathways, retinoic acid-induced HL-60 myeloid differentiation selectively depends on activating ERK but not the other two MAPK pathways, JNK/SAPK or p38, with no apparent cross talk between pathways. Furthermore, the striking ability of polyoma middle T antigens to promote retinoic acid-induced differentiation appears to utilize ERK, but not JNK/SPK or p38 signaling.
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References
Breitman, T. R.; Selonick, S. E.; Collins, S. J. Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid. Proc. Natl. Acad. Sci. USA 77:2936–2940; 1980.
Cohen, P. The search for physiological substrates of MAP and SAP kinases in mammalian cells. Trends Cell Biol. 7:353–361; 1997.
Collins, S. J.; Gallo, R. C.; Gallagher, R. E. Continuous growth and differentiation of human myeloid leukaemic cells in suspension culture. Nature (Lond) 270:347–349; 1977.
Flynn, P. J.; Miller, W. J.; Weisdorf, D. J.; Arthur, D. C.; Brunning, R.; Branda, R. F. Retinoic acid treatment of acute promyelocytic leukemia: in vitro and in vivo observations. Blood 62:1211–1217; 1983.
Gudas, L. J. Retinoids and vertebrate development. J. Biol. Chem. 22:15399–15402; 1994.
Jho, E. H.; Davis, R. J.; Malbon, C. C. C-Jun amino-terminal kinase is regulated by G-alpha-12G-alpha-13 and obligate for differentiation of P19 embryonal carcinoma cells by retinoic acid. J. Biol. Chem. 272:24468–24474; 1997.
Kanakaraj, P.; Schafer, P. H.; Cavender, D. E.; Wu, Y.; Ngo, K.; Grealish, P. E.; Wadsworth, S. A.; Peterson, P. A.; Siekierka, J. J.; Fung-Leung, W. P. Interleukin (IL)-1 receptor-associated kinase (IRAK) requirement for optimal induction of multiple IL-1 signaling pathways and IL-6 production. J. Exp. Med. 187:2073–2079; 1998.
Katagiri, K.; Hattori, S.; Nakamura, S.; Yamamoto, T.; Yoshida, T.; Katagiri, T. Activation of Ras and formation of GAP complex during TPA-induced monocytic differentiation of HL-60 cells. Blood 84:1780–1789; 1994.
Kita, Y.; Kimura, K. D.; Kobayashi, M.; Ihara, S.; Kaibuchi, K.; Shinya, K.; Ui, M.; Iba, H. Microinjection of activated phosphatidylinositol-3 kinase induces process outgrowth in rat PC12 cells through the Rac-JNK signal transduction pathway. J. Cell Sci. 111:907–915; 1998.
Kyriakis, J. M.; Avruch, J. Sounding the alarm: protein kinase cascades activated by stress and inflammation. J. Biol. Chem. 271:24313–24316; 1996.
Lee, H. Y.; Walsh, G. L.; Dawson, M. I.; Hong, W. K.; Kurie, J. M. Alltrans retinoic acid inhibits Jun N-terminal kinase-dependent signaling pathways. J. Biol. Chem. 273:7066–7071; 1998.
Lee, J. C.; Young, P. R. Role of CSBP/p38/RK stress response kinase in LPS and cytokine signaling mechanisms. J. Leukocyte Biol. 59:152–157; 1996.
Lim, C. P.; Jain, N.; Cao, X. Stress-induced immediate-early gene, egr-1, involves activation of p38-JNK1. Oncogene 16:2915–2926; 1998.
Mangelsdorf, D. J.; Kazukiko, U.; Evans, R. M. The retinoid receptors. In: Sporn, M. B.; Roberts, A.; Goodman, D. S., ed. The Retinoids. 2nd ed. New York: Raven Press; 1994:319–349.
Meves, A.; Peus, D.; Pittelkow, M. R. Okadaic acid and pervanadate regulate EGFR-ERK, MKK3-p38 and JNK signaling pathways in keratinocytes. J. Dermatol. Sci. 16(Suppl. 1):s46; 1998.
Nagata, Y.; Moriguchi, T.; Nishida, E.; Todokoro, K. Activation of p38 MAP kinase pathway by erythropoietin and interleukin-3. Blood 90:929–934; 1997.
Platko, J. D.; Forbes, M. E.; Varvayanis, S.; Williams, M. N.; Brooks III, S. C.; Cherington, V.; Yen, A. Polyoma middle-T antigen in HL-60 cells accelerates hematopoietic myeloid and monocytic cell differentiation. Exp. Cell Res. 238:42–50; 1998.
Smith, D. B.; Johnson, K. S. Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase. Gene 67:31–40; 1988.
Xing, J.; Kornhauser, J. M.; Xia, Z.; Thiele, E. A.; Greenberg, M. Nerve growth factor activates extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways to stimulate CREB serine 133 phosphorylation. Mol. Cell. Biol. 18:1946–1955; 1998.
Xue, L.; Lucocq, J. M. Low extracellular pH induces activation of ERK 2, JNK, and p38 in A431 and Swiss 3T3 cells. Biochem. Biophys. Res. Comm. 241:236–242; 1997.
Yen, A. HL-60 cells as a model of growth control and differentiation: the significance of variant cells. Hematol. Rev. 4:5–46; 1990.
Yen, A.; Cherington, V.; Schaffhausen, B.; Marks, K.; Varvayanis, S. Transformation defective polyoma middle-T antigen mutants defective in PLCγ, PI-3 or SRC kinase activation promote retinoic acid induced cell differentiation like wild type middle-T. Exp. Cell. Res. 248:538–551; 1999.
Yen, A.; Forbes, M.; deGala, G.; Fishbaugh, J. Control of HL-60 cell differentiation lineage specificity: a late event occurring after precommitment. Cancer Res. 47:129–134; 1987.
Yen, A.; Forbes, M. E.; Varvayanis, S.; Tykocincki, M. L.; Groger, R. K.; Platko, J. D. C-FMS dependent HL-60 cell differentiation and regulation of RB gene expression. J. Cell. Physiol. 157:379–391; 1993.
Yen, A.; Reece, S. L.; Albright, K. L. Dependence of HL-60 myeloid cell differentiation on continuous and split retinoic acid exposures: precommitment memory associated with altered nuclear structure. J. Cell. Physiol. 118:277–286; 1984.
Yen, A.; Roberson, M. S.; Varvayanis, S.; Lee, A. T. Retinoic acid induced mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase-dependent MAP kinase activation needed to elicit HL-60 cell differentiation and growth arrest. Cancer Res. 58:3163–3172; 1998.
Yen, A.; Williams, M.; Platko, J. D.; Der, C.; Hisaka, M. Expression of activated RAF accelerates cell differentiation and RB protein down regulation but not hypophosphorylation. Eur. J. Cell. Biol. 65:103–113; 1994.
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Yen, A., Roberson, M.S. & Varvayanis, S. Retinoic acid selectively activates the ERK2 but not JNK/SAPK or P38 map kinases when inducing myeloid differentiation. In Vitro Cell.Dev.Biol.-Animal 35, 527–532 (1999). https://doi.org/10.1007/s11626-999-0063-z
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DOI: https://doi.org/10.1007/s11626-999-0063-z