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Hepatitis B Virus Core Promoter A1762T/G1764A (TA)/T1753A/T1768A Mutations Contribute to Hepatocarcinogenesis by Deregulating Skp2 and P53.
Dig Dis Sci. 2015 May; 60(5):1315-24.DD

Abstract

BACKGROUND AND AIM

Hepatitis B virus core promoter (CP) mutations can increase risk of hepatocellular carcinoma. The CP region overlaps with the HBV X (HBx) gene, which has been associated with hepatocarcinogenesis. The cyclin kinase inhibitor P53 is an important regulator of cell cycle progression. We determined whether HBx mutants that result from mutations in the CP deregulate P53.

METHODS

A HBx combination (combo) mutant with changes in the CP region that corresponded to A1762T/G1764A (TA), T1753A, and T1768A was constructed and expressed in L-02 and Hep3B cells. The effects of CP mutations on expression and degradation of P53, and the effects on cell cycle progression and proliferation were analyzed.

RESULTS

The combo mutant decreased levels of P53 and increased cyclin D1 expression, accelerated P53 degradation in L-02 cells, accelerated cell cycle progression, and increased expression of S-phase kinase-associated protein 2 (Skp2) in L-02 and Hep3B cells. Silencing of Skp2 abrogated the effects of CP mutations on P53 expression. The kinetics of P53 expression correlated with changes in cell cycle distribution.

CONCLUSIONS

The HBx mutant with a combination of CP mutations can up-regulate Skp2, which then down-regulates P53 via ubiquitin-mediated proteasomal degradation, increasing the risk of hepatocellular carcinoma.

Authors+Show Affiliations

Hepatobiliary Surgery Department, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600, TianHe Road, TianHe District, Guangzhou City, 510630, China.No 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

Language

eng

PubMed ID

25567052

Citation

Yan, Jian, et al. "Hepatitis B Virus Core Promoter A1762T/G1764A (TA)/T1753A/T1768A Mutations Contribute to Hepatocarcinogenesis By Deregulating Skp2 and P53." Digestive Diseases and Sciences, vol. 60, no. 5, 2015, pp. 1315-24.
Yan J, Yao Z, Hu K, et al. Hepatitis B Virus Core Promoter A1762T/G1764A (TA)/T1753A/T1768A Mutations Contribute to Hepatocarcinogenesis by Deregulating Skp2 and P53. Dig Dis Sci. 2015;60(5):1315-24.
Yan, J., Yao, Z., Hu, K., Zhong, Y., Li, M., Xiong, Z., & Deng, M. (2015). Hepatitis B Virus Core Promoter A1762T/G1764A (TA)/T1753A/T1768A Mutations Contribute to Hepatocarcinogenesis by Deregulating Skp2 and P53. Digestive Diseases and Sciences, 60(5), 1315-24. https://doi.org/10.1007/s10620-014-3492-9
Yan J, et al. Hepatitis B Virus Core Promoter A1762T/G1764A (TA)/T1753A/T1768A Mutations Contribute to Hepatocarcinogenesis By Deregulating Skp2 and P53. Dig Dis Sci. 2015;60(5):1315-24. PubMed PMID: 25567052.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hepatitis B Virus Core Promoter A1762T/G1764A (TA)/T1753A/T1768A Mutations Contribute to Hepatocarcinogenesis by Deregulating Skp2 and P53. AU - Yan,Jian, AU - Yao,Zhicheng, AU - Hu,Kunpeng, AU - Zhong,Yuesi, AU - Li,Mingliang, AU - Xiong,Zhiyong, AU - Deng,Meihai, Y1 - 2015/01/08/ PY - 2014/04/19/received PY - 2014/12/11/accepted PY - 2015/1/9/entrez PY - 2015/1/9/pubmed PY - 2015/7/28/medline SP - 1315 EP - 24 JF - Digestive diseases and sciences JO - Dig. Dis. Sci. VL - 60 IS - 5 N2 - BACKGROUND AND AIM: Hepatitis B virus core promoter (CP) mutations can increase risk of hepatocellular carcinoma. The CP region overlaps with the HBV X (HBx) gene, which has been associated with hepatocarcinogenesis. The cyclin kinase inhibitor P53 is an important regulator of cell cycle progression. We determined whether HBx mutants that result from mutations in the CP deregulate P53. METHODS: A HBx combination (combo) mutant with changes in the CP region that corresponded to A1762T/G1764A (TA), T1753A, and T1768A was constructed and expressed in L-02 and Hep3B cells. The effects of CP mutations on expression and degradation of P53, and the effects on cell cycle progression and proliferation were analyzed. RESULTS: The combo mutant decreased levels of P53 and increased cyclin D1 expression, accelerated P53 degradation in L-02 cells, accelerated cell cycle progression, and increased expression of S-phase kinase-associated protein 2 (Skp2) in L-02 and Hep3B cells. Silencing of Skp2 abrogated the effects of CP mutations on P53 expression. The kinetics of P53 expression correlated with changes in cell cycle distribution. CONCLUSIONS: The HBx mutant with a combination of CP mutations can up-regulate Skp2, which then down-regulates P53 via ubiquitin-mediated proteasomal degradation, increasing the risk of hepatocellular carcinoma. SN - 1573-2568 UR - https://www.unboundmedicine.com/medline/citation/25567052/Hepatitis_B_Virus_Core_Promoter_A1762T/G1764A__TA_/T1753A/T1768A_Mutations_Contribute_to_Hepatocarcinogenesis_by_Deregulating_Skp2_and_P53_ L2 - https://doi.org/10.1007/s10620-014-3492-9 DB - PRIME DP - Unbound Medicine ER -