ik3-2, a relative to ik3-1/Cables, is involved in both p53-mediated and p53-independent apoptotic pathways.
ik3-2 is a close relative to ik3-1/Cables, an associator with cdk3 and cdk5. ik3-1/Cables has been identified to be a candidate tumor suppressor for colon and head/neck cancers. In agreement, it has been pointed out that ik3-1/Cables is a regulator for both p53- and p73-induced apoptosis [J. Biol. Chem. 277 (2002) 2951] although ectopic expression of ik3-1/Cables does not induce apoptosis. Here we show that adenovirus-mediated overexpression of ik3-2 results in apoptosis of p53-intact U2OS cells. ik3-2 binds to p53 in vivo and ectopic coexpression of ik3-2 enhances apoptosis induced by adenovirus-mediated expression of p53. Furthermore, ectopic expression of ik3-2 results in apoptosis of primary p53/Mdm2- and p53/ARF-null mouse embryo fibroblasts, indicating that ik3-2-induced apoptosis is partially p53-independent. Both the highly conserved C-terminal cyclin box-homologous domain (ik3-2-C) and the N-terminal region consisting of 70 amino acids (ik3-2-N) are responsible for ik3-2-mediated enhancement of p53-induced apoptosis. In contrast, ik3-2-induced p53-independent apoptosis is mediated through ik3-2-N. We thus identified ik3-2 as a proapoptotic factor involved in both p53-mediated and p53-independent apoptotic pathways.
Matsuoka
Masaaki
M
Department of Pharmacology, University of KEIO School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. sakimatu@sc.itc.keio.ac.jp
Sudo
Haruka
H
Tsuji
Keitaro
K
Sato
Hiroko
H
Kurita
Megumi
M
Suzuki
Hiroaki
H
Nishimoto
Ikuo
I
Ogata
Etsuro
E
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D016213:Cyclins / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000196:embryology / Q000378:metabolism; D051379:Mice; D012516:Osteosarcoma / Q000378:metabolism*; D010750:Phosphoproteins; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C486568:CABLES1 protein, human; C411580:Cables1 protein, mouse; C457759:Cables2 protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016213:Cyclins; D010750:Phosphoproteins; D016159:Tumor Suppressor Protein p53