PTEN gene transcription is stimulated by TP53, EGR1, PPARG, ATF2, MAF1, and inhibited by NR2E1, SALL4, MECOM, SNAI1, SNAI2, JUN

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R-HSA-8944104
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Homo sapiens
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PTEN (phosphatase and tensin homolog deleted in chromosome 10) is a tumor suppressor gene that is deleted or mutated in a variety of human cancers. TP53 (p53) stimulates PTEN transcription (Stambolic et al. 2000, Singh et al. 2002). PTEN, acting as a negative regulator of PI3K/AKT signaling, affects cell survival, cell cycling, proliferation and migration. PTEN regulates TP53 stability by inhibiting AKT-mediated activation of TP53 ubiquitin ligase MDM2, and thus enhances TP53 transcriptional activity and its own transcriptional activation by TP53. Beside their cross-regulation, PTEN and TP53 can interact and cooperate to regulate survival or apoptotic phenomena (Stambolic et al. 2000, Singh et al. 2002, Nakanishi et al. 2014).
In response to UV induced DNA damage, PTEN transcription is stimulated by binding of the transcription factor EGR1 to the promoter region of PTEN (Virolle et al. 2001).
PTEN transcription is also stimulated by binding of the activated nuclear receptor PPARG (PPARgamma) to peroxisome proliferator response elements (PPREs) in the promoter of the PTEN gene (Patel et al. 2001), binding of the ATF2 transcription factor, activated by stress kinases of the p38 MAPK family, to ATF response elements in the PTEN gene promoter (Shen et al. 2006) and by the transcription factor MAF1 (Li et al. 2016).
NR2E1 (TLX) associated with transcription repressors binds the evolutionarily conserved TLX consensus site in the PTEN promoter. NR2E1 inhibits PTEN transcription by associating with various transcriptional repressors, probably in a cell type or tissue specific manner. PTEN transcription is inhibited when NR2E1 forms a complex with ATN1 (atrophin-1) (Zhang et al. 2006, Yokoyama et al. 2008), KDM1A (LSD1) histone methyltransferase containing CoREST complex (Yokoyama et al. 2008), or histone deacetylases HDAC3, HDAC5 or HDAC7 (Sun et al. 2007).
Binding of the transcriptional repressor SNAI1 (Snail1) to the PTEN promoter represses PTEN transcription. SNAI1-mediated repression of PTEN transcription may require phosphorylation of SNAI1 on serine residue S246. Binding of SNAI1 to the PTEN promoter increases in response to ionizing radiation and is implicated in SNAI1-mediated resistance to gamma-radiation induced apoptosis (Escriva et al. 2008). Binding of another Slug/Snail family member SNAI2 (SLUG) to the PTEN gene promoter also represses PTEN transcription (Uygur et al. 2015).
Binding of JUN to the AP-1 element in the PTEN gene promoter (Hettinger et al. 2007) inhibits PTEN transcription. JUN partner FOS is not needed for JUN-mediated downregulation of PTEN (Vasudevan et al. 2007).
Binding of the transcription factor SALL4 to the PTEN gene promoter (Yang et al. 2008) and SALL4-medaited recruitment of the transcriptional repressor complex NuRD (Lu et al. 2009, Gao et al. 2013), containing histone deacetylases HDAC1 and HDAC2, inhibits the PTEN gene transcription. SALL4-mediated recruitment of DNA methyltransferases (DNMTs) is also implicated in transcriptional repression of PTEN (Yang et al. 2012).
Binding of the transcription factor MECOM (EVI1) to the PTEN gene promoter and MECOM-mediated recruitment of polycomb repressor complexes containing BMI1 (supposedly PRC1.4), and EZH2 (PRC2) leads to repression of PTEN transcription (Song et al. 2009, Yoshimi et al. 2011).

Literature References
PubMed ID Title Journal Year
19884659 The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells

Song, LB, Li, J, Liao, WT, Feng, Y, Yu, CP, Hu, LJ, Kong, QL, Xu, LH, Zhang, X, Liu, WL, Li, MZ, Zhang, L, Kang, TB, Fu, LW, Huang, WL, Xia, YF, Tsao, SW, Li, M, Band, V, Band, H, Shi, QH, Zeng, YX, Zeng, MS

J. Clin. Invest. 2009
21289308 Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins

Yoshimi, A, Goyama, S, Watanabe-Okochi, N, Yoshiki, Y, Nannya, Y, Nitta, E, Arai, S, Sato, T, Shimabe, M, Nakagawa, M, Imai, Y, Kitamura, T, Kurokawa, M

Blood 2011
16676006 c-Jun promotes cellular survival by suppression of PTEN

Hettinger, K, Vikhanskaya, F, Poh, MK, Lee, MK, de Belle, I, Zhang, JT, Reddy, SA, Sabapathy, K

Cell Death Differ. 2007
11545734 Regulation of PTEN transcription by p53

Stambolic, V, MacPherson, D, Sas, D, Lin, Y, Snow, B, Jang, Y, Benchimol, S, Mak, TW

Mol. Cell 2001
11378386 Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN

Patel, L, Pass, I, Coxon, P, Downes, CP, Smith, SA, MacPhee, CH

Curr. Biol. 2001
16702404 Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1

Zhang, CL, Zou, Y, Yu, RT, Gage, FH, Evans, RM

Genes Dev. 2006
18172008 Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis

Escrivà, M, Peiró, S, Herranz, N, Villagrasa, P, Dave, N, Montserrat-Sentís, B, Murray, SA, Francí, C, Gridley, T, Virtanen, I, García de Herreros, A

Mol. Cell. Biol. 2008
24718924 The tumor suppressor PTEN interacts with p53 in hereditary cancer (Review)

Nakanishi, A, Kitagishi, Y, Ogura, Y, Matsuda, S

Int. J. Oncol. 2014
26910647 MAF1 suppresses AKT-mTOR signaling and liver cancer through activation of PTEN transcription

Li, Y, Tsang, CK, Wang, S, Li, XX, Yang, Y, Fu, L, Huang, W, Li, M, Wang, HY, Zheng, XF

Hepatology 2016
11959846 p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas

Singh, B, Reddy, PG, Goberdhan, A, Walsh, C, Dao, S, Ngai, I, Chou, TC, O-Charoenrat, P, Levine, AJ, Rao, PH, Stoffel, A

Genes Dev. 2002
11781575 The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling

Virolle, T, Adamson, ED, Baron, V, Birle, D, Mercola, D, Mustelin, T, de Belle, I

Nat. Cell Biol. 2001
16418168 Up-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) mediates p38 MAPK stress signal-induced inhibition of insulin signaling. A cross-talk between stress signaling and insulin signaling in resistin-treated human endothelial cells

Shen, YH, Zhang, L, Gan, Y, Wang, X, Wang, J, LeMaire, SA, Coselli, JS, Wang, XL

J. Biol. Chem. 2006
17974977 Suppression of PTEN expression is essential for antiapoptosis and cellular transformation by oncogenic Ras

Vasudevan, KM, Burikhanov, R, Goswami, A, Rangnekar, VM

Cancer Res. 2007
19440552 Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex

Lu, J, Jeong, HW, Kong, N, Yang, Y, Carroll, J, Luo, HR, Silberstein, LE, Yupoma, LE, Chai, L

PLoS One 2009
18487508 SALL4 is a key regulator of survival and apoptosis in human leukemic cells

Yang, J, Chai, L, Gao, C, Fowles, TC, Alipio, Z, Dang, H, Xu, D, Fink, LM, Ward, DC, Ma, Y

Blood 2008
22128185 Stem cell gene SALL4 suppresses transcription through recruitment of DNA methyltransferases

Yang, J, Corsello, TR, Ma, Y

J. Biol. Chem. 2012
17873065 Orphan nuclear receptor TLX recruits histone deacetylases to repress transcription and regulate neural stem cell proliferation

Sun, G, Yu, RT, Evans, RM, Shi, Y

Proc. Natl. Acad. Sci. U.S.A. 2007
25728608 SLUG is a direct transcriptional repressor of PTEN tumor suppressor

Uygur, B, Abramo, K, Leikina, E, Vary, C, Liaw, L, Wu, WS

Prostate 2015
18391013 Transrepressive function of TLX requires the histone demethylase LSD1

Yokoyama, A, Takezawa, S, Schüle, R, Kitagawa, H, Kato, S

Mol. Cell. Biol. 2008
23287862 Targeting transcription factor SALL4 in acute myeloid leukemia by interrupting its interaction with an epigenetic complex

Gao, C, Dimitrov, T, Yong, KJ, Tatetsu, H, Jeong, HW, Luo, HR, Bradner, JE, Tenen, DG, Chai, L

Blood 2013
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