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PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis

 Min-Sik Lee  ;  Man-Hyung Jeong  ;  Hyun-Woo Lee  ;  Hyun-Ji Han  ;  Aram Ko  ;  Stephen M. Hewitt  ;  Jae-Hoon Kim  ;  Kyung-Hee Chun  ;  Joon-Yong Chung  ;  Cheolju Lee  ;  Hanbyoul Cho  ;  Jaewhan Song 
 NATURE COMMUNICATIONS, Vol.6 : 7769, 2015 
Journal Title
Issue Date
Adenocarcinoma/genetics ; Adenocarcinoma/metabolism ; Adenocarcinoma/pathology ; Carcinogenesis/genetics ; Carcinoma/genetics* ; Carcinoma/metabolism ; Carcinoma/pathology ; Carcinoma, Squamous Cell/genetics ; Carcinoma, Squamous Cell/metabolism ; Carcinoma, Squamous Cell/pathology ; Cell Line, Tumor ; Cell Movement ; Cervical Intraepithelial Neoplasia/genetics* ; Cervical Intraepithelial Neoplasia/metabolism ; Feedback, Physiological ; Female ; Gene Expression Regulation, Neoplastic* ; HeLa Cells ; Humans ; Immunohistochemistry ; In Vitro Techniques ; Mutation ; Nerve Tissue Proteins/metabolism* ; PTEN Phosphohydrolase/genetics* ; PTEN Phosphohydrolase/metabolism ; Phosphatidylinositol 3-Kinases/genetics* ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoproteins ; Phosphorylation ; Prognosis ; Protein Processing, Post-Translational ; Proto-Oncogene Proteins c-akt/metabolism* ; Receptor, Epidermal Growth Factor/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Ribonucleoproteins/metabolism* ; TOR Serine-Threonine Kinases/metabolism ; Ubiquitination ; Uterine Cervical Neoplasms/genetics* ; Uterine Cervical Neoplasms/metabolism
The activity of the phosphatase and tensin homologue (PTEN) is known to be suppressed via post-translational modification. However, the mechanism and physiological significance by which post-translational modifications lead to PTEN suppression remain unclear. Here we demonstrate that PTEN destabilization is induced by EGFR- or oncogenic PI3K mutation-mediated AKT activation in cervical cancer. EGFR/PI3K/AKT-mediated ubiquitination and degradation of PTEN are dependent on the MKRN1 E3 ligase. These processes require the stabilization of MKRN1 via AKT-mediated phosphorylation. In cervical cancer patients with high levels of pAKT and MKRN1 expression, PTEN protein levels are low and correlate with a low 5-year survival rate. Taken together, our results demonstrate that PI3K/AKT signals enforce positive-feedback regulation by suppressing PTEN function.
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1. College of Medicine (의과대학) > Dept. of Obstetrics and Gynecology (산부인과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jae Hoon(김재훈) ORCID logo https://orcid.org/0000-0001-6599-7065
Chun, Kyung Hee(전경희) ORCID logo https://orcid.org/0000-0002-9867-7321
Cho, Hanbyoul(조한별) ORCID logo https://orcid.org/0000-0002-6177-1648
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