This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, J. Articles by Huang, C. Search for Related Content PubMed PubMed Citation Articles by Wang, J. Articles by Huang, C.

Loss of Tumor Suppressor p53 Decreases PTEN Expression and Enhances Signaling Pathways Leading to Activation of Activator Protein 1 and Nuclear Factor B Induced by UV Radiation

¹ Nelson Institute of Environmental Medicine, School of Medicine, New York University, Tuxedo, New York; ² Tumor Immunology and Gene Therapy Center, Eastern Hospital of Hepatobiliary Surgery, Second Military Medical University, Shanghai, China; and ³ Department of Surgery, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China

Requests for reprints: Chuanshu Huang, Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987. Phone: 845-731-3519; Fax: 845-351-2320; E-mail: chuanshu{at}env.med.nyu.edu.

Transcription factor p53 and phosphatase PTEN are two tumor suppressors that play essential roles in suppression of carcinogenesis. However, the mechanisms by which p53 mediates anticancer activity and the relationship between p53 and PTEN are not well understood. In the present study, we found that pretreatment of mouse epidermal Cl41 cells with pifithrin-, an inhibitor for p53-dependent transcriptional activation, resulted in a marked increase in UV-induced activation of activator protein 1 (AP-1) and nuclear factor B (NF-B). Consistent with activation of AP-1 and NF-B, pifithrin- was also able to enhance the UV-induced phosphorylation of c-Jun-NH₂-kinases (JNK) and p38 kinase, whereas it did not show any effect on phosphorylation of extracellular signal-regulated kinases. Furthermore, the UV-induced signal activation, including phosphorylation of JNK, p38 kinase, Akt, and p70^S6K, was significantly enhanced in p53-deficient cells (p53–/–), which can be reversed by p53 reconstitution. In addition, knockdown of p53 expression by its small interfering RNA also caused the elevation of AP-1 activation and Akt phosphorylation induced by UV radiation. These results show that p53 has a suppressive activity on the cell signaling pathways leading to activation of AP-1 and NF-B in cell response to UV radiation. More importantly, deficiency of p53 expression resulted in a decrease in PTEN protein expression, suggesting that p53 plays a critical role in the regulation of PTEN expression. In addition, overexpression of wild-type PTEN resulted in inhibition of UV-induced AP-1 activity. Because PTEN is a well-known phosphatase involved in the regulation of phosphatidylinositol 3-kinase (PI-3K)/Akt signaling pathway, taken together with the evidence that PI-3K/Akt plays an important role in the activation of AP-1 and NF-B during tumor development, we anticipate that inhibition of AP-1 and NF-B by tumor suppressor p53 seems to be mediated via PTEN, which may be a novel mechanism involved in anticancer activity of p53 protein.

This article has been cited by other articles:

				S. Han, J. D. Ritzenthaler, Y. Zheng, and J. Roman PPAR{beta}/{delta} agonist stimulates human lung carcinoma cell growth through inhibition of PTEN expression: the involvement of PI3K and NF-{kappa}B signals Am J Physiol Lung Cell Mol Physiol, June 1, 2008; 294(6): L1238 - L1249. [Abstract] [Full Text] [PDF]

				D. Yao, C. L. Alexander, J. A. Quinn, W.-C. Chan, H. Wu, and D. A. Greenhalgh Fos cooperation with PTEN loss elicits keratoacanthoma not carcinoma, owing to p53/p21WAF-induced differentiation triggered by GSK3{beta} inactivation and reduced AKT activity J. Cell Sci., May 15, 2008; 121(10): 1758 - 1769. [Abstract] [Full Text] [PDF]

				W. Luo, J. Liu, J. Li, D. Zhang, M. Liu, J. K. Addo, S. Patil, L. Zhang, J. Yu, J. K. Buolamwini, et al. Anti-cancer Effects of JKA97 Are Associated with Its Induction of Cell Apoptosis via a Bax-dependent and p53-independent Pathway J. Biol. Chem., March 28, 2008; 283(13): 8624 - 8633. [Abstract] [Full Text] [PDF]

				D. Zhang, J. Li, L. Song, W. Ouyang, J. Gao, and C. Huang A JNK1/AP-1-Dependent, COX-2 Induction Is Implicated in 12-O-Tetradecanoylphorbol-13-Acetate-Induced Cell Transformation through Regulating Cell Cycle Progression Mol. Cancer Res., January 1, 2008; 6(1): 165 - 174. [Abstract] [Full Text] [PDF]

				T. Tamguney and D. Stokoe New insights into PTEN J. Cell Sci., December 1, 2007; 120(23): 4071 - 4079. [Abstract] [Full Text] [PDF]

				D. J. Groskreutz, M. M. Monick, T. O. Yarovinsky, L. S. Powers, D. E. Quelle, S. M. Varga, D. C. Look, and G. W. Hunninghake Respiratory Syncytial Virus Decreases p53 Protein to Prolong Survival of Airway Epithelial Cells J. Immunol., September 1, 2007; 179(5): 2741 - 2747. [Abstract] [Full Text] [PDF]

				C. Blanco-Aparicio, O. Renner, J. F.M. Leal, and A. Carnero PTEN, more than the AKT pathway Carcinogenesis, July 1, 2007; 28(7): 1379 - 1386. [Abstract] [Full Text] [PDF]

				L. Song, J. Li, J. Ye, G. Yu, J. Ding, D. Zhang, W. Ouyang, Z. Dong, S. O. Kim, and C. Huang p85{alpha} Acts as a Novel Signal Transducer for Mediation of Cellular Apoptotic Response to UV Radiation Mol. Cell. Biol., April 1, 2007; 27(7): 2713 - 2731. [Abstract] [Full Text] [PDF]

				D. Zhang, L. Song, J. Li, K. Wu, and C. Huang Coordination of JNK1 and JNK2 Is Critical for GADD45{alpha} Induction and Its Mediated Cell Apoptosis in Arsenite Responses J. Biol. Chem., November 10, 2006; 281(45): 34113 - 34123. [Abstract] [Full Text] [PDF]

				Y. Tang and C. Eng p53 Down-Regulates Phosphatase and Tensin Homologue Deleted on Chromosome 10 Protein Stability Partially through Caspase-Mediated Degradation in Cells with Proteasome Dysfunction. Cancer Res., June 15, 2006; 66(12): 6139 - 6148. [Abstract] [Full Text] [PDF]