Page 45 - ebook

[F. Others] F-22

SPINT2 is a key effector of DNMT1 to regulate the entry into

senescence

Minseok Sim¹,²,³, Seongki Min¹,²,³, Gyesoon Yoon¹,²,³*

¹Department of Biochemistry & Molecular Biology, Ajou University School of Medicine, Suwon 16499, Korea,

²Inflamm-aging Translational Research Center, Ajou University Medical Center, Suwon 16499, Korea, ³Department

of Biomedical Science, The Graduate School, Ajou University, Suwon 16499, Korea

As senescence develops, cells sequentially acquire diverse senescent phenotypes along with simultaneous stage-
specific gene reprogramming. DNA methyltransferase 1 (DNMT1) is an DNA modifying enzyme that controls

expression patterns of various genes by catalyzing the transfer of methyl groups to cytosine residues of specific
CpG islands in the gene promoter regions. Decreased DNMT1 expression was also observed in oxidative stress-

induced senescence (OSIS) of HDF. With our effort to identify downstream effectors of DNMT1 to regulate
senescence, SPINT2 was expected to be a potential downstream effector of DNMT1 to modulate senescence through

suppressing HGF/c-Met signaling. In this study, The negative correlation between DNMT1 and SPINT2 was also
observed in oxidative stress induced senescence model and replicative model. In addition, DNMT1 was proved to

be an upstream regulator of SPINT2. To determine how DNMT1 regulates SPINT2, a luciferase reporter vector with
SPINT2 promoter DNA(2 kb length) was produced. I identified an important region of the SPINT2 promoter which

is regulated by DNMT1. SPINT2 is known to regulates the HGF/c-Met signaling pathway. SPINT2 was overexpressed,
c-Met phosphorylation status was decreased. Knockdown of c-Met induced senescence phenotype. I concluded
that the reduction of DNMT1 increases SPINT2 and inhibited the c-Met signaling, thereby inducing senescence

phenotype.