Lysophosphatidic acid inhibits melanocyte proliferation via cell cycle arrest.
Lysophosphatidic acid (LPA) is a well-known mitogen in various cell types. However, we found that LPA inhibits melanocyte proliferation. Thus, we further investigated the possible signaling pathways involved in melanocyte growth inhibition. We first examined the regulation of the three major subfamilies of mitogen-activated protein (MAP) kinases and of the Akt pathway by LPA. The activations of extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) were observed in concert with the inhibition of melanocyte proliferation by LPA, whereas p38 MAP kinase and Akt were not influenced by LPA. However, the specific inhibition of the ERK or JNK pathways by PD98059 or D-JNKI1, respectively, did not restore the antiproliferative effect. We next examined changes in the expression of cell cycle related proteins. LPA decreased cyclin D1 and cyclin D2 levels but increased p21(WAF1/CIP1) (p21) and p27KIP1 (p27) levels, which are known inhibitors of cyclin-dependent kinase. Flow cytometric analysis showed the inhibition of DNA synthesis by a reduction in the S phase and an increase in the G0/G1 phase of the cell cycle. Our results suggest that LPA induces cell cycle arrest by regulating the expressions of cell cycle related proteins.
Kim
Dong-Seok
DS
Research Division for Human Life Sciences, Seoul National University, Seoul, Korea.
Park
Seo-Hyoung
SH
Kim
Sung-Eun
SE
Kwon
Sun-Bang
SB
Park
Eun-Sang
ES
Youn
Sang-Woong
SW
Park
Kyoung-Chan
KC
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D008246:Lysophospholipids / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008544:Melanocytes / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology
D005419:Flavonoids; D006131:Growth Inhibitors; D008246:Lysophospholipids; D010455:Peptides; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C478085:D-JNKI-1; C032881:lysophosphatidic acid; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one