Activated Notch1 Inhibits P53-induced Apoptosis and Sustains Transformation by Human Papillomavirus Type 16 E6 and E7 Oncogenes Through a PI3K-PKB/Akt-dependent Pathway

Overview

Journal J Virol

Publisher American Society for Microbiology

Date 2003 May 28

PMID 12768030

Citations 68

Authors

Pradip Nair

Kumaravel Somasundaram

Sudhir Krishna

Affiliations

Soon will be listed here.

Abstract

Activated Notch1 (AcN1) alleles cooperate with oncogenes from DNA tumor viruses in transformation of epithelial cells. AcN1 signaling has pleiotropic effects, and suggested oncogenic roles include driving proliferation through cyclin D1 or the generation of resistance to apoptosis on matrix withdrawal through a phosphatidylinositol 3-kinase (PI3K)-PKB/Akt-dependent pathway. Here, we extend the antiapoptotic role for AcN1 by showing inhibition of p53-induced apoptosis and transactivation. Chemical inhibitors of the PI3K pathway block AcN1-induced inhibition of p53-dependent apoptosis and nuclear localization of Hdm2. We show that expression of wild-type p53 does not inhibit synergistic transformation by AcN1 and human papillomavirus E6 and E7 oncogenes. We suggest that activation of Notch signaling may serve as an additional mechanism to inhibit wild-type p53 function in papillomavirus-associated neoplasia.

Citing Articles

Exploring the potential link between human papillomavirus infection and coronary artery disease: a review of shared pathways and mechanisms.

Saha D, Dutta P, Rebello K, Shankar A, Chakraborty A Mol Cell Biochem. 2025; .

PMID: 40045143 DOI: 10.1007/s11010-025-05236-9.

Canonical and noncanonical NOTCH signaling in the nongenetic resistance of cancer: distinct and concerted control.

Huang X, Chen W, Wang Y, Shytikov D, Wang Y, Zhu W Front Med. 2025; 19(1):23-52.

PMID: 39745621 DOI: 10.1007/s11684-024-1107-1.

Unveiling HPV's hidden link: Cardiovascular diseases and the viral intrigue.

Dutta P, Saha D, Earle M, Prasad C, Singh M, Darswal M Indian Heart J. 2024; 76(1):1-5.

PMID: 38387552 PMC: 10943540. DOI: 10.1016/j.ihj.2024.02.001.

HPV E6/E7: insights into their regulatory role and mechanism in signaling pathways in HPV-associated tumor.

Peng Q, Wang L, Zuo L, Gao S, Jiang X, Han Y Cancer Gene Ther. 2023; 31(1):9-17.

PMID: 38102462 DOI: 10.1038/s41417-023-00682-3.

A replicative recombinant HPV16 E7 expression virus upregulates CD36 in C33A cells.

Shao Y, Wang P, Zheng Y, Cui H, Lou Z, Li S Front Microbiol. 2023; 14:1259510.

PMID: 37795297 PMC: 10545859. DOI: 10.3389/fmicb.2023.1259510.

References

Zagouras P, Stifani S, Blaumueller C, Carcangiu M, Artavanis-Tsakonas S . Alterations in Notch signaling in neoplastic lesions of the human cervix. Proc Natl Acad Sci U S A. 1995; 92(14):6414-8. PMC: 41528. DOI: 10.1073/pnas.92.14.6414. View

Lehman T, Modali R, Boukamp P, Stanek J, BENNETT W, Welsh J . p53 mutations in human immortalized epithelial cell lines. Carcinogenesis. 1993; 14(5):833-9. DOI: 10.1093/carcin/14.5.833. View

Hickman E, Bates S, Vousden K . Perturbation of the p53 response by human papillomavirus type 16 E7. J Virol. 1997; 71(5):3710-8. PMC: 191520. DOI: 10.1128/JVI.71.5.3710-3718.1997. View

Daniel B, Rangarajan A, Mukherjee G, Vallikad E, Krishna S . The link between integration and expression of human papillomavirus type 16 genomes and cellular changes in the evolution of cervical intraepithelial neoplastic lesions. J Gen Virol. 1997; 78 ( Pt 5):1095-101. DOI: 10.1099/0022-1317-78-5-1095. View

Kubbutat M, Jones S, Vousden K . Regulation of p53 stability by Mdm2. Nature. 1997; 387(6630):299-303. DOI: 10.1038/387299a0. View

Capobianco A, Zagouras P, Blaumueller C, Artavanis-Tsakonas S, Bishop J . Neoplastic transformation by truncated alleles of human NOTCH1/TAN1 and NOTCH2. Mol Cell Biol. 1997; 17(11):6265-73. PMC: 232477. DOI: 10.1128/MCB.17.11.6265. View

Datta S, Dudek H, Tao X, Masters S, Fu H, Gotoh Y . Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997; 91(2):231-41. DOI: 10.1016/s0092-8674(00)80405-5. View

Gray G, Mann R, Mitsiadis E, Henrique D, Carcangiu M, Banks A . Human ligands of the Notch receptor. Am J Pathol. 1999; 154(3):785-94. PMC: 1866435. DOI: 10.1016/S0002-9440(10)65325-4. View

Nair P, Nair K, Jayaprakash P, Pillai M . Decreased programmed cell death in the uterine cervix associated with high risk human papillomavirus infection. Pathol Oncol Res. 1999; 5(2):95-103. DOI: 10.1053/paor.1999.0161. View

10.

Somasundaram K . Tumor suppressor p53: regulation and function. Front Biosci. 2000; 5:D424-37. DOI: 10.2741/somasund. View

11.

Marchenko N, Zaika A, Moll U . Death signal-induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling. J Biol Chem. 2000; 275(21):16202-12. DOI: 10.1074/jbc.275.21.16202. View

12.

Hietanen S, Lain S, Krausz E, Blattner C, Lane D . Activation of p53 in cervical carcinoma cells by small molecules. Proc Natl Acad Sci U S A. 2000; 97(15):8501-6. PMC: 26977. DOI: 10.1073/pnas.97.15.8501. View

13.

Paramio J, Segrelles C, Lain S, Lane D, Lane E, Jorcano J . p53 is phosphorylated at the carboxyl terminus and promotes the differentiation of human HaCaT keratinocytes. Mol Carcinog. 2001; 29(4):251-62. DOI: 10.1002/1098-2744(200012)29:4<251::aid-mc1007>3.0.co;2-o. View

14.

Rangarajan A, Syal R, Selvarajah S, Chakrabarti O, Sarin A, Krishna S . Activated Notch1 signaling cooperates with papillomavirus oncogenes in transformation and generates resistance to apoptosis on matrix withdrawal through PKB/Akt. Virology. 2001; 286(1):23-30. DOI: 10.1006/viro.2001.0867. View

15.

Ronchini C, Capobianco A . Induction of cyclin D1 transcription and CDK2 activity by Notch(ic): implication for cell cycle disruption in transformation by Notch(ic). Mol Cell Biol. 2001; 21(17):5925-34. PMC: 87311. DOI: 10.1128/MCB.21.17.5925-5934.2001. View

16.

Aster J, Pear W . Notch signaling in leukemia. Curr Opin Hematol. 2001; 8(4):237-44. DOI: 10.1097/00062752-200107000-00010. View

17.

Mayo L, Donner D . A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci U S A. 2001; 98(20):11598-603. PMC: 58775. DOI: 10.1073/pnas.181181198. View

18.

Huang L, Chou Y, Chao S, Chen T, Lee T . p53 and p21 expression in precancerous lesions and carcinomas of the uterine cervix: overexpression of p53 predicts poor disease outcome. Gynecol Oncol. 2001; 83(2):348-54. DOI: 10.1006/gyno.2001.6397. View

19.

Brazil D, Hemmings B . Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci. 2001; 26(11):657-64. DOI: 10.1016/s0968-0004(01)01958-2. View

20.

Schuler M, Green D . Mechanisms of p53-dependent apoptosis. Biochem Soc Trans. 2001; 29(Pt 6):684-8. DOI: 10.1042/0300-5127:0290684. View