한빛사논문
- 조회260
Jung-Jin Park 1,6, Su Jin Lee 1,6, Minwoo Baek 1, Ok-Jun Lee 2, Seungyoon Nam 3, Jaehong Kim 4, Jin Young Kim 5, Eun-Young Shin 1,* and Eung-Gook Kim 1,*
1Department of Biochemistry, Chungbuk National University, College of Medicine and Medical Research Center, Cheongju 28644, Republic of Korea.
2Department of Pathology, Chungbuk National University, College of Medicine and Medical Research Center, Cheongju 28644, Republic of Korea.
3Department of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences and Technology (GAIHST), Gachon University, Incheon 21565, Republic of Korea.
4Department of Biochemistry, College of Medicine, Gachon University, Incheon 21999, Republic of Korea.
5Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Republic of Korea.
6These authors contributed equally: Jung-Jin Park, Su Jin Lee.
*Corresponding authors: correspondence to Eun-Young Shin or Eung-Gook Kim
Abstract
Cellular senescence, a hallmark of aging, is pathogenically linked to the development of aging-related diseases. This study demonstrates that FRMD6, an upstream component of the Hippo/YAP signaling cascade, is a key regulator of senescence. Proteomic analysis revealed that FRMD6 is upregulated in senescent IMR90 fibroblasts under various senescence-inducing conditions. Silencing FRMD6 mitigated the senescence of IMR90 cells, suggesting its requirement in senescence. Conversely, the overexpression of FRMD6 alone induced senescence in cells and in lung tissue, establishing a causal link. The elevated FRMD6 levels correlated well with increased levels of the inhibitory phosphorylated YAP/TAZ. We identified cellular communication network factor 3 (CCN3), a key component of the senescence-associated secretory phenotype regulated by YAP, whose administration attenuated FRMD6-induced senescence in a dose-dependent manner. Mechanistically, FRMD6 interacted with and activated MST kinase, which led to YAP/TAZ inactivation. The expression of FRMD6 was regulated by the p53 and SMAD transcription factors in senescent cells. Accordingly, the expression of FRMD6 was upregulated by TGF-β treatment that activates those transcription factors. In TGF-β-treated IMR90 cells, FRMD6 mainly segregated with p21, a senescence marker, but rarely segregated with α-SMA, a myofibroblast marker, which suggests that FRMD6 has a role in directing cells towards senescence. Similarly, in TGF-β-enriched environments, such as fibroblastic foci (FF) from patients with idiopathic pulmonary fibrosis, FRMD6 co-localized with p16 in FF lining cells, while it was rarely detected in α-SMA-positive myofibroblasts that are abundant in FF. In sum, this study identifies FRMD6 as a novel regulator of senescence and elucidates the contribution of the FRMD6-Hippo/YAP-CCN3 axis to senescence.
논문정보
- Research article
- 2024년 06월 (BRIC 등록일 2024-07-25)
- 국내 연구진
- 의약학 > 분자세포의학
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