Melanoma cell growth inhibition by betagamma-CAT, which is a novel non-lens betagamma-crystallin and trefoil factor complex from frog Bombina maxima skin.
In vertebrates, non-lens betagamma-crystallins are widely expressed in various tissues but their functions are unknown. The molecular mechanisms of trefoil factors, initiators of mucosal healing and being greatly involved in tumorigenesis, have remained elusive. betagamma-CAT, which is responsible for the potent hemolytic activity and lethal toxicity on mice of frog Bombina maxima skin secretions, is the first example of a non-lens betagamma-crystallin and trefoil factor complex. Its alpha- and beta-subunits show significant sequence homology to human Absent In Melanoma 1 and trefoil factors, respectively. Here, we showed that betagamma-CAT triggered two types of cellular responses in human melanoma cells. On one hand, the protein (25-200 pM) was able to stimulate cell migration in melanoma A375 cells. On the other hand, it inhibited cell proliferation by delaying S-G2/M cell phase transition. Blockade of the cell cycle was associated with increased p21/WAF1 expression, and reduced amounts of Cdc2 and Cdc25C. betagamma-CAT also reduced Cdc2 function by increasing the level of inactivated phospho-Cdc2. In addition, the expression of JunB, a well-known cell proliferation inhibitor, was significantly up-regulated. These results provide the first evidence of an anti-proliferative role for a non-lens betagamma-crystallin member and action mechanism via association with a trefoil factor.
He
Ying Ying
YY
Biotoxin Units, Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
Liu
Shu Bai
SB
Lee
Wen Hui
WH
Zhang
Yun
Y
D000818:Animals; D001001:Anura / Q000502:physiology*; D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003459:Crystallins / Q000633:toxicity*; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000633:toxicity*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000737:chemistry*; D000071164:Trefoil Factor-2; D015854:Up-Regulation; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D003459:Crystallins; D019926:Cyclin B; D050759:Cyclin-Dependent Kinase Inhibitor p21; D010455:Peptides; D016755:Proto-Oncogene Proteins c-jun; D000071164:Trefoil Factor-2; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases