The PI3K-Akt pathway regulates calpain 6 expression, proliferation, and apoptosis.
The calpains are a family of cysteine proteases involved in some biological processes whose activities are highly dependent on Ca(2+). Calpain 6 (CAPN6), one member of the family, is unique in that it lacks the active-site cysteine residues for protease activity. According to the data that CAPN6 was up-regulated in the Akt transformed mouse embryonic fibroblast cells by cDNA chip, the mechanisms underlying elevated CAPN6 expression by PI3K-Akt signaling pathway and its biological functions were studied. The results showed that CAPN6 was down-regulated on transcriptional and post-transcriptional levels by the PI3K inhibitor or Akt deletion. CAPN6 protein was stabilized by PI3K-GSK-3β pathway. Deleted CAPN6 promoters activity were assessed by dual-luciferase reporter system, and the founding indicated that -93/+200 DNA fragment was the core promoter of it. Transcription factor binding sites in the CAPN6 promoter were mutated and the results showed that AP1, Oct-1, and FoxD3 were the critical transcription factors in regulation of CAPN6 expression. In addition, CAPN6 promoted cancer cell proliferation and inhibited its apoptosis. The finding demonstrates that CAPN6 is regulated by the PI3K-Akt signaling pathway and provides evidence that it may be a therapeutic target of cancer.
Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Yonglei
Y
Liu
Chuanzhong
C
Mei
Lidong
L
Sun
Xin
X
Li
Mingzhu
M
Liu
Liying
L
Wang
Zengxia
Z
Li
Peng
P
Yin
Chao
C
Zhao
Yinghong
Y
Shi
Shuangjian
S
Qiu
Jia
J
Fan
Xiliang
X
Zha
D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D005347:Fibroblasts / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D050811:Octamer Transcription Factor-1 / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
D002154:Calpain; D051858:Forkhead Transcription Factors; D050811:Octamer Transcription Factor-1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D018808:Transcription Factor AP-1; C101757:Foxd3 protein, mouse; C403234:Capn6 protein, mouse