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Mutant human tumor suppressor p53 modulates the activation of mitogen-activated protein kinase and nuclear factor-kappaB, but not c-Jun N-terminal kinase and activated protein-1.
Mol Carcinog. 2006 Jan; 45(1):26-37.MC

Abstract

The roles of the mitogen-activated kinase protein (MAPK) pathway, nuclear factor-kappa B (NF-kappaB), and activator protein-1 (AP-1) in cellular responses to growth factors and mitogen are well established. However, the manner by which these proliferative pathways are affected by the tumor suppressor protein p53 is not fully understood. We report here the results of an investigation of the status of p53 on two human melanoma cell lines with wild-type p53 (SK-Mel-186) or mutant p53 (SK-Mel-110). The basal levels of the activated extracellular-signal regulated kinases 1 and 2 (ERK1/2) were high in cells with wild-type p53, but low in cells with mutant p53. The 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced activation of ERK1/2 through the phosphorylation of threonine and tyrosine at 202 and 204, respectively, was demonstrated in both cell lines, however, in a discrete manner. TPA-induced activation of ERK1/2 was sustained in wild-type p53 cells, while only a transient activation was seen in mutant p53 cells. Inhibition of MAPK kinase (MEK), an upstream kinase, by U0126, blocked TPA-induced activation of ERK1/2 in wild-type p53 cells and in mutant p53 cells. Treatment of wild-type p53 (SK-Mel 186) cells with small interfering RNA (siRNA) of p53 displayed a transient induction of activation of ERK1/2 following TPA treatment, indicating that p53 has a role in the regulation of the activation of ERK1/2. NF-kappaB activity decreased significantly in cells with wild-type p53, while enhanced NF-kappaB activity was evident in cells with mutant p53. The expression of either wild-type or mutant p53 had a similar effect on TPA-induced Jun N-terminal kinase (JNK) activation, indicating specificity for the ERK pathway. Similarly, AP-1 binding activity showed a transient variation in both cell lines after TPA treatment but with different kinetics. These observations suggest that both wild-type and mutant p53 can modulate the activation pathways for ERK1/2, and NF-kappaB distinctively, while modulating the pathways of JNK and AP-1 similarly. These differences may influence cellular processes such as proliferation, differentiation, and apoptosis.

Authors+Show Affiliations

Department of Neurosurgery, New York Medical College, Valhalla, New York 10595, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

16267831

Citation

Gulati, Anthony P., et al. "Mutant Human Tumor Suppressor P53 Modulates the Activation of Mitogen-activated Protein Kinase and Nuclear factor-kappaB, but Not c-Jun N-terminal Kinase and Activated Protein-1." Molecular Carcinogenesis, vol. 45, no. 1, 2006, pp. 26-37.
Gulati AP, Yang YM, Harter D, et al. Mutant human tumor suppressor p53 modulates the activation of mitogen-activated protein kinase and nuclear factor-kappaB, but not c-Jun N-terminal kinase and activated protein-1. Mol Carcinog. 2006;45(1):26-37.
Gulati, A. P., Yang, Y. M., Harter, D., Mukhopadhyay, A., Aggarwal, B. B., Aggarwal, B. A., Benzil, D. L., Whysner, J., Albino, A. P., Murali, R., & Jhanwar-Uniyal, M. (2006). Mutant human tumor suppressor p53 modulates the activation of mitogen-activated protein kinase and nuclear factor-kappaB, but not c-Jun N-terminal kinase and activated protein-1. Molecular Carcinogenesis, 45(1), 26-37.
Gulati AP, et al. Mutant Human Tumor Suppressor P53 Modulates the Activation of Mitogen-activated Protein Kinase and Nuclear factor-kappaB, but Not c-Jun N-terminal Kinase and Activated Protein-1. Mol Carcinog. 2006;45(1):26-37. PubMed PMID: 16267831.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutant human tumor suppressor p53 modulates the activation of mitogen-activated protein kinase and nuclear factor-kappaB, but not c-Jun N-terminal kinase and activated protein-1. AU - Gulati,Anthony P, AU - Yang,Yang-Ming, AU - Harter,David, AU - Mukhopadhyay,Asok, AU - Aggarwal,Bharat B, AU - Aggarwal,Bharat A, AU - Benzil,Deborah L, AU - Whysner,John, AU - Albino,Anthony P, AU - Murali,Raj, AU - Jhanwar-Uniyal,Meena, PY - 2005/11/4/pubmed PY - 2006/3/29/medline PY - 2005/11/4/entrez SP - 26 EP - 37 JF - Molecular carcinogenesis JO - Mol Carcinog VL - 45 IS - 1 N2 - The roles of the mitogen-activated kinase protein (MAPK) pathway, nuclear factor-kappa B (NF-kappaB), and activator protein-1 (AP-1) in cellular responses to growth factors and mitogen are well established. However, the manner by which these proliferative pathways are affected by the tumor suppressor protein p53 is not fully understood. We report here the results of an investigation of the status of p53 on two human melanoma cell lines with wild-type p53 (SK-Mel-186) or mutant p53 (SK-Mel-110). The basal levels of the activated extracellular-signal regulated kinases 1 and 2 (ERK1/2) were high in cells with wild-type p53, but low in cells with mutant p53. The 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced activation of ERK1/2 through the phosphorylation of threonine and tyrosine at 202 and 204, respectively, was demonstrated in both cell lines, however, in a discrete manner. TPA-induced activation of ERK1/2 was sustained in wild-type p53 cells, while only a transient activation was seen in mutant p53 cells. Inhibition of MAPK kinase (MEK), an upstream kinase, by U0126, blocked TPA-induced activation of ERK1/2 in wild-type p53 cells and in mutant p53 cells. Treatment of wild-type p53 (SK-Mel 186) cells with small interfering RNA (siRNA) of p53 displayed a transient induction of activation of ERK1/2 following TPA treatment, indicating that p53 has a role in the regulation of the activation of ERK1/2. NF-kappaB activity decreased significantly in cells with wild-type p53, while enhanced NF-kappaB activity was evident in cells with mutant p53. The expression of either wild-type or mutant p53 had a similar effect on TPA-induced Jun N-terminal kinase (JNK) activation, indicating specificity for the ERK pathway. Similarly, AP-1 binding activity showed a transient variation in both cell lines after TPA treatment but with different kinetics. These observations suggest that both wild-type and mutant p53 can modulate the activation pathways for ERK1/2, and NF-kappaB distinctively, while modulating the pathways of JNK and AP-1 similarly. These differences may influence cellular processes such as proliferation, differentiation, and apoptosis. SN - 0899-1987 UR - https://www.unboundmedicine.com/medline/citation/16267831/Mutant_human_tumor_suppressor_p53_modulates_the_activation_of_mitogen_activated_protein_kinase_and_nuclear_factor_kappaB_but_not_c_Jun_N_terminal_kinase_and_activated_protein_1_ L2 - https://doi.org/10.1002/mc.20149 DB - PRIME DP - Unbound Medicine ER -