Skp2 enhances polyubiquitination and degradation of TIS21/BTG2/PC3, tumor suppressor protein, at the downstream of FoxM1.
TIS21(/BTG2/PC3) has been shown to work as a pan-cell cycle inhibitor and a negative regulator of cyclin B1/cdk1 and forkhead box M1 (FoxM1). Moreover, loss of TIS21 expression has been suggested as an early event in carcinogenesis of thymus, prostate, kidney, and liver. However, there is no report yet what regulates the in vivo stability of TIS21 protein. Here, TIS21 was found to be a target of ubiquitin ligase, S phase kinase associated protein 2 (Skp2), the expression of which was regulated by FoxM1. Leucine rich repeat (LRR) domain of Skp2 could bind to TIS21 C-terminus and facilitated TIS21 degradation via ubiquitin-proteasome pathway. Skp2 without LRR and C-terminus deleted TIS21 (TIS21DeltaC) failed to interact with each other, and failure of their interaction prolonged half-life of TIS21 protein. Furthermore, in vivo function of TIS21, inhibition of cell growth, was regulated by expressions of Skp2 and FoxM1; It was significantly enhanced by knock down of Skp2 expression in the TIS21 adenovirus infected cells, whereas it was significantly ameliorated by co-expression of FoxM1 with TIS21. These data indicate that TIS21 is a novel target of SCF-Skp2 ubiquitin ligase, which is regulated by expression of FoxM1.
Park
Tae Jun
TJ
Department of Biochemistry and Molecular Biology, Brain Korea 21 Division of Cell Transformation and Restoration, Ajou University, School of Medicine, Suwon, 443-721, Republic of Korea.
Kim
Ji Yeon
JY
Park
Su Hyun
SH
Kim
Hong Seok
HS
Lim
In Kyoung
IK
D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000819:agonists / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D025821:Polyubiquitin / Q000187:drug effects / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000187:drug effects / Q000378:metabolism*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000819:agonists / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects / Q000502:physiology
D015853:Cysteine Proteinase Inhibitors; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D017874:Immediate-Early Proteins; D007976:Leupeptins; D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins; D025821:Polyubiquitin; C070114:BTG2 protein, human; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde