Activation of Rac1 and the p38 Mitogen-activated Protein Kinase Pathway in Response to All-trans-retinoic Acid

Yazan Alsayed, Shahab Uddin, Nadim Mahmud, Fatima Lekmine, Dhananjaya V. Kalvakolanu, Saverio Minucci, Gary Bokoch, Leonidas C. Platanias

Research output: Contribution to journalArticle

132 Citations (Scopus)

Abstract

Several signaling pathways are activated by all-transretinoic acid (RA) to mediate induction of differentiation and apoptosis of malignant cells. In the present study we provide evidence that the p38 MAP kinase pathway is activated in a RA-dependent manner in the NB-4, acute promyelocytic leukemia, and the MCF-7, breast carcinoma, cell lines. RA treatment of cells induces a time- and dose-dependent phosphorylation of p38, and such phosphorylation results in activation of its catalytic domain. p38 activation is not inducible by RA in a variant NB4 cell line, NB-4.007/6, which is resistant to the effects of RA, suggesting a role for this pathway in the induction of RA responses. Our data also demonstrate that the small G-protein Rac1 is activated by RA and functions as an upstream regulator of p38 activation, whereas the MAPKAPK-2 serine kinase is a downstream effector for the RA-activated p38. To obtain information on the functional role of the Rac1/p38/MAPKAPK-2 pathway in RA signaling, the effects of pharmacological inhibition of p38 on RA-induced gene transcription and cell differentiation were determined. Our results indicate that treatment of cells with the SB203580 inhibitor does not inhibit RA-dependent gene transcription via retinoic acid response elements or induction of Stat1 protein expression. However, treatment with SB203580 or SB202190 strongly enhances RA-dependent induction of cell differentiation and RA-regulated growth inhibitory responses. Altogether, our findings demonstrate that the Rac1/p38 MAP kinase pathway is activated in a RA-dependent manner and exhibits negative regulatory effects on the induction of differentiation.

Original languageEnglish
Pages (from-to)4012-4019
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number6
DOIs
Publication statusPublished - Feb 9 2001

Fingerprint

p38 Mitogen-Activated Protein Kinases
Tretinoin
MAP Kinase Signaling System
Chemical activation
Cells
Cell Differentiation
Phosphorylation
Cell Line
Transcription
Acute Promyelocytic Leukemia
Monomeric GTP-Binding Proteins
Protein-Serine-Threonine Kinases
Response Elements
Genes
Catalytic Domain
Pharmacology
Apoptosis
Breast Neoplasms
Acids
Growth

ASJC Scopus subject areas

  • Biochemistry

Cite this

Activation of Rac1 and the p38 Mitogen-activated Protein Kinase Pathway in Response to All-trans-retinoic Acid. / Alsayed, Yazan; Uddin, Shahab; Mahmud, Nadim; Lekmine, Fatima; Kalvakolanu, Dhananjaya V.; Minucci, Saverio; Bokoch, Gary; Platanias, Leonidas C.

In: Journal of Biological Chemistry, Vol. 276, No. 6, 09.02.2001, p. 4012-4019.

Research output: Contribution to journalArticle

Alsayed, Y, Uddin, S, Mahmud, N, Lekmine, F, Kalvakolanu, DV, Minucci, S, Bokoch, G & Platanias, LC 2001, 'Activation of Rac1 and the p38 Mitogen-activated Protein Kinase Pathway in Response to All-trans-retinoic Acid', Journal of Biological Chemistry, vol. 276, no. 6, pp. 4012-4019. https://doi.org/10.1074/jbc.M007431200
Alsayed, Yazan ; Uddin, Shahab ; Mahmud, Nadim ; Lekmine, Fatima ; Kalvakolanu, Dhananjaya V. ; Minucci, Saverio ; Bokoch, Gary ; Platanias, Leonidas C. / Activation of Rac1 and the p38 Mitogen-activated Protein Kinase Pathway in Response to All-trans-retinoic Acid. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 6. pp. 4012-4019.
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AU - Lekmine, Fatima

AU - Kalvakolanu, Dhananjaya V.

AU - Minucci, Saverio

AU - Bokoch, Gary

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AB - Several signaling pathways are activated by all-transretinoic acid (RA) to mediate induction of differentiation and apoptosis of malignant cells. In the present study we provide evidence that the p38 MAP kinase pathway is activated in a RA-dependent manner in the NB-4, acute promyelocytic leukemia, and the MCF-7, breast carcinoma, cell lines. RA treatment of cells induces a time- and dose-dependent phosphorylation of p38, and such phosphorylation results in activation of its catalytic domain. p38 activation is not inducible by RA in a variant NB4 cell line, NB-4.007/6, which is resistant to the effects of RA, suggesting a role for this pathway in the induction of RA responses. Our data also demonstrate that the small G-protein Rac1 is activated by RA and functions as an upstream regulator of p38 activation, whereas the MAPKAPK-2 serine kinase is a downstream effector for the RA-activated p38. To obtain information on the functional role of the Rac1/p38/MAPKAPK-2 pathway in RA signaling, the effects of pharmacological inhibition of p38 on RA-induced gene transcription and cell differentiation were determined. Our results indicate that treatment of cells with the SB203580 inhibitor does not inhibit RA-dependent gene transcription via retinoic acid response elements or induction of Stat1 protein expression. However, treatment with SB203580 or SB202190 strongly enhances RA-dependent induction of cell differentiation and RA-regulated growth inhibitory responses. Altogether, our findings demonstrate that the Rac1/p38 MAP kinase pathway is activated in a RA-dependent manner and exhibits negative regulatory effects on the induction of differentiation.

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