FGF12 Positively Regulates Keratinocyte Proliferation by Stabilizing MDM2 and Inhibiting p53 Activity in Psoriasis

doi:10.1002/advs.202400107

科研成果详情

题名	FGF12 Positively Regulates Keratinocyte Proliferation by Stabilizing MDM2 and Inhibiting p53 Activity in Psoriasis
作者	Wang, Nan1,2; Xu, Xiejun1; Guan, Fangqian1; Lin, Yifan1; Ye, Yizhou1; Zhou, Jie 1; Feng, Jianjun1; Li, Sihang1; Ye, Junbo1; Tang, Zhouhao3; Gao, Wenjie1; Sun, Bohao 4; Shen, Yingjie 5; Sun, Li6; Song, Yonghuan7; Jin, Litai1; Li, Xiaokun1; Cong, Weitao1; Zhu, Zhongxin 1
发表日期	2024-09-05
发表期刊	Advanced Science 影响因子和分区
语种	英语
原始文献类型	Article ; Early Access
关键词	FGF12 MDMD2 p53 proliferation psoriasis
其他关键词	CLINICAL-FEATURES ; SKIN INFLAMMATION ; PATHWAY ; PATHOGENESIS ; MECHANISMS ; ROLES ; AXIS
摘要	Psoriasis is a chronic skin disease characterized by abnormal proliferation and inflammation of epidermal keratinocytes. Fibroblast growth factor 12 (FGF12) is implicated in the regulation of diverse cellular signals; however, its precise mechanism in psoriasis requires further investigation. In this study, high expression of FGF12 is observed in the epidermis of skin lesion in psoriasis patients and imiquimod (IMQ)-induced psoriasis like-dermatitis. Moreover, specific loss of FGF12 in keratinocytes in IMQ-induced psoriasis model alleviates psoriasis-like symptoms and reduces proliferation. In vitro RNA sequencing demonstrates that knockdown of FGF12 effectively arrests the cell cycle, inhibits cell proliferation, and predominantly regulates the p53 signaling pathway. Mechanistically, FGF12 is selectively bound to the RING domain of MDM2, thus partially inhibiting the binding of beta-Trcp to MDM2. This interaction inhibits beta-Trcp-induced-K48 ubiquitination degradation of MDM2, thereby suppressing the activity of the p53 signaling pathway, which results in excessive cell proliferation. Last, the alleviatory effect of FGF12 deficiency on psoriasis progression is reversed by p53 knockdown. In summary, these findings provide valuable insights into the mechanisms by which FGF12 suppresses p53 signaling in keratinocytes, exacerbating the development of psoriasis. This positive regulatory loop highlights the potential of FGF12 as a therapeutic target to manage psoriasis. FGF12 is upregulated in the epidermis of patients with psoriasis and the imiquimod-induced mouse model. Keratinocyte-specific deletion of FGF12 ameliorates the psoriasiform phenotype. Mechanistically, FGF12 is selectively bound to the RING domain of MDM2, thus partially inhibiting the binding of beta-Trcp to MDM2. This interaction inhibits beta-Trcp-induced-K48 ubiquitination degradation of MDM2, thereby suppressing the activity of the p53 signaling pathway, which results in excessive cell proliferation. image
资助项目	Project of Wenzhou Association For Science and Technology; National Nature Science Foundation of China [82272284, 82273560, 82304004]; Zhejiang Provincial Natural Science Foundation [LZ21H020002, LY22H110002]; Zhejiang Province Medical and Health Science Program [2022KY198]; Scientific Research Center of Wenzhou Medical University; [kjfw0227]
出版者	WILEY
ISSN	2198-3844
EISSN	2198-3844
卷号	11 期号:39
DOI	10.1002/advs.202400107
页数	19
WOS类目	Chemistry, Multidisciplinary ; Nanoscience & Nanotechnology ; Materials Science, Multidisciplinary
WOS研究方向	Chemistry ; Science & Technology - Other Topics ; Materials Science
WOS记录号	WOS:001306134400001
收录类别	SCIE ; EI ; PUBMED ; SCOPUS
EI入藏号	20243617004584
EI主题词	Cell signaling
EI分类号	101.1 ; 101.3 ; 101.7 ; 102.1 ; 102.1.2 ; 102.2.1 ; 103 ; 914.1 Accidents and Accident Prevention
URL	查看原文
PubMed ID	39234815
SCOPUSEID	2-s2.0-85203050950
通讯作者地址	[Li, Xiaokun;Cong, Weitao;Zhu, Zhongxin]Wenzhou Med Univ, Sch Pharmaceut Sci, Wenzhou 325035, Peoples R China.
Scopus学科分类	Medicine (miscellaneous);Chemical Engineering (all);Materials Science (all);Biochemistry, Genetics and Molecular Biology (miscellaneous);Engineering (all);Physics and Astronomy (all)
SCOPUS_ID	SCOPUS_ID:85203050950
引用统计
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/218595
专题	药学院（分析测试中心）附属第一医院附属第一医院_风湿免疫科第二临床医学院、附属第二医院、育英儿童医院
通讯作者	Li, Xiaokun; Cong, Weitao; Zhu, Zhongxin
作者单位	1.Wenzhou Med Univ, Sch Pharmaceut Sci, Wenzhou 325035, Peoples R China; 2.Hangzhou Med Coll, Zhejiang Prov Peoples Hosp, Affiliated Peoples Hosp, Dept Pharm, Hangzhou 310014, Zhejiang, Peoples R China; 3.Wenzhou Med Univ, Affiliated Hosp & Yuying Childrens Hosp 2, Dept Cardiol, Wenzhou 325027, Peoples R China; 4.Zhejiang Univ, Affiliated Hosp 2, Dept Pathol, Hangzhou 310009, Peoples R China; 5.Huzhou Univ, Sch Life Sci, Huzhou 313000, Peoples R China; 6.Wenzhou Med Univ, Affiliated Hosp 1, Dept Rheumatol & Immunol, Wenzhou 325000, Peoples R China; 7.Wenzhou Med Univ, Affiliated Hosp & Yuying Childrens Hosp 2, Dept Orthopaed, Wenzhou 325027, Peoples R China
第一作者单位	药学院（分析测试中心）
通讯作者单位	药学院（分析测试中心）
第一作者的第一单位	药学院（分析测试中心）
推荐引用方式 GB/T 7714	Wang, Nan,Xu, Xiejun,Guan, Fangqian,et al. FGF12 Positively Regulates Keratinocyte Proliferation by Stabilizing MDM2 and Inhibiting p53 Activity in Psoriasis[J]. Advanced Science,2024,11(39).
APA	Wang, Nan., Xu, Xiejun., Guan, Fangqian., Lin, Yifan., Ye, Yizhou., ... & Zhu, Zhongxin. (2024). FGF12 Positively Regulates Keratinocyte Proliferation by Stabilizing MDM2 and Inhibiting p53 Activity in Psoriasis. Advanced Science, 11(39).
MLA	Wang, Nan,et al."FGF12 Positively Regulates Keratinocyte Proliferation by Stabilizing MDM2 and Inhibiting p53 Activity in Psoriasis".Advanced Science 11.39(2024).