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Salicylic acid reverses phorbol 12-myristate-13-acetate (PMA)- and tumor necrosis factor alpha (TNFalpha)-induced insulin receptor substrate 1 (IRS1) serine 307 phosphorylation and insulin resistance in human embryonic kidney 293 (HEK293) cells.
J Biol Chem 2003; 278(1):180-6JB

Abstract

Salicylates, including aspirin, have been shown to improve insulin sensitivity both in human and animal models. Although it has been suggested that salicylates sensitize insulin action by inhibiting IkappaB kinase beta (IKKbeta), the detailed mechanisms remain unclear. Protein kinase C isoforms and tumor necrosis factor alpha (TNFalpha) signaling pathways are well described mediators of insulin resistance; they are implicated in the activation of IKKbeta and the subsequent inhibition of proximal insulin signaling via insulin receptor substrate 1 (IRS1) and Akt. This study investigated the effect of salicylic acid on phorbol 12-myristate 13-acetate (PMA)- and TNFalpha-induced insulin resistance in a human embryonic kidney 293 (HEK293) cell line stably expressing recombinant human IRS1. The results showed that both PMA and TNFalpha inhibited insulin-induced Akt phosphorylation and promoted IRS1 phosphorylation on Ser-307. Salicylic acid pretreatment completely reversed the effects of PMA and TNFalpha on both Akt and IRS1. Whereas PMA activated protein kinase C isoforms and IKKbeta, TNFalpha activated neither. On the other hand, both PMA and TNFalpha activated the c-Jun N-terminal kinase (JNK), which has been reported to directly phosphorylate IRS1 Ser-307. SP600125, a JNK inhibitor, prevented PMA and TNFalpha-induced IRS1 Ser-307 phosphorylation. Finally, salicylic acid inhibited JNK activation induced by both PMA and TNFalpha. Taken together, these observations suggest that salicylic acid can reverse the inhibitory effects of TNFalpha on insulin signaling via an IKKbeta-independent mechanism(s), potentially involving the inhibition of JNK activation. The role of JNK in salicylic acid-mediated insulin sensitization, however, requires further validation because the JNK inhibitor SP600125 appears to have other nonspecific activity in addition to inhibiting JNK activity.

Authors+Show Affiliations

Department of Molecular Endocrinology-Diabetes, Merck Research Laboratories, Rahway, New Jersey 07065, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

12409308

Citation

Jiang, Guoqiang, et al. "Salicylic Acid Reverses Phorbol 12-myristate-13-acetate (PMA)- and Tumor Necrosis Factor Alpha (TNFalpha)-induced Insulin Receptor Substrate 1 (IRS1) Serine 307 Phosphorylation and Insulin Resistance in Human Embryonic Kidney 293 (HEK293) Cells." The Journal of Biological Chemistry, vol. 278, no. 1, 2003, pp. 180-6.
Jiang G, Dallas-Yang Q, Liu F, et al. Salicylic acid reverses phorbol 12-myristate-13-acetate (PMA)- and tumor necrosis factor alpha (TNFalpha)-induced insulin receptor substrate 1 (IRS1) serine 307 phosphorylation and insulin resistance in human embryonic kidney 293 (HEK293) cells. J Biol Chem. 2003;278(1):180-6.
Jiang, G., Dallas-Yang, Q., Liu, F., Moller, D. E., & Zhang, B. B. (2003). Salicylic acid reverses phorbol 12-myristate-13-acetate (PMA)- and tumor necrosis factor alpha (TNFalpha)-induced insulin receptor substrate 1 (IRS1) serine 307 phosphorylation and insulin resistance in human embryonic kidney 293 (HEK293) cells. The Journal of Biological Chemistry, 278(1), pp. 180-6.
Jiang G, et al. Salicylic Acid Reverses Phorbol 12-myristate-13-acetate (PMA)- and Tumor Necrosis Factor Alpha (TNFalpha)-induced Insulin Receptor Substrate 1 (IRS1) Serine 307 Phosphorylation and Insulin Resistance in Human Embryonic Kidney 293 (HEK293) Cells. J Biol Chem. 2003 Jan 3;278(1):180-6. PubMed PMID: 12409308.
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TY - JOUR T1 - Salicylic acid reverses phorbol 12-myristate-13-acetate (PMA)- and tumor necrosis factor alpha (TNFalpha)-induced insulin receptor substrate 1 (IRS1) serine 307 phosphorylation and insulin resistance in human embryonic kidney 293 (HEK293) cells. AU - Jiang,Guoqiang, AU - Dallas-Yang,Qing, AU - Liu,Franklin, AU - Moller,David E, AU - Zhang,Bei B, Y1 - 2002/10/29/ PY - 2002/11/1/pubmed PY - 2003/2/11/medline PY - 2002/11/1/entrez SP - 180 EP - 6 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 278 IS - 1 N2 - Salicylates, including aspirin, have been shown to improve insulin sensitivity both in human and animal models. Although it has been suggested that salicylates sensitize insulin action by inhibiting IkappaB kinase beta (IKKbeta), the detailed mechanisms remain unclear. Protein kinase C isoforms and tumor necrosis factor alpha (TNFalpha) signaling pathways are well described mediators of insulin resistance; they are implicated in the activation of IKKbeta and the subsequent inhibition of proximal insulin signaling via insulin receptor substrate 1 (IRS1) and Akt. This study investigated the effect of salicylic acid on phorbol 12-myristate 13-acetate (PMA)- and TNFalpha-induced insulin resistance in a human embryonic kidney 293 (HEK293) cell line stably expressing recombinant human IRS1. The results showed that both PMA and TNFalpha inhibited insulin-induced Akt phosphorylation and promoted IRS1 phosphorylation on Ser-307. Salicylic acid pretreatment completely reversed the effects of PMA and TNFalpha on both Akt and IRS1. Whereas PMA activated protein kinase C isoforms and IKKbeta, TNFalpha activated neither. On the other hand, both PMA and TNFalpha activated the c-Jun N-terminal kinase (JNK), which has been reported to directly phosphorylate IRS1 Ser-307. SP600125, a JNK inhibitor, prevented PMA and TNFalpha-induced IRS1 Ser-307 phosphorylation. Finally, salicylic acid inhibited JNK activation induced by both PMA and TNFalpha. Taken together, these observations suggest that salicylic acid can reverse the inhibitory effects of TNFalpha on insulin signaling via an IKKbeta-independent mechanism(s), potentially involving the inhibition of JNK activation. The role of JNK in salicylic acid-mediated insulin sensitization, however, requires further validation because the JNK inhibitor SP600125 appears to have other nonspecific activity in addition to inhibiting JNK activity. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/12409308/Salicylic_acid_reverses_phorbol_12_myristate_13_acetate__PMA___and_tumor_necrosis_factor_alpha__TNFalpha__induced_insulin_receptor_substrate_1__IRS1__serine_307_phosphorylation_and_insulin_resistance_in_human_embryonic_kidney_293__HEK293__cells_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=12409308 DB - PRIME DP - Unbound Medicine ER -