alpha 1-Adrenergic receptor subtypes differentially control the cell cycle of transfected CHO cells through a cAMP-dependent mechanism involving p27Kip1.
Three distinct subtypes of alpha(1)-adrenergic receptors (alpha(1)A-, alpha(1)B-, and alpha(1)D-AR) play a prominent role in cell growth. However, little is known about subtype-specific effects on cell proliferation. The activation of alpha(1)A- or alpha(1)B-AR inhibits serum-promoted cell proliferation, whereas alpha(1)D-AR activation does not show such an inhibitory effect. Notably, cell-cycle progression was blocked at G(1)/S transition after activation of alpha(1)A/alpha(1)B-AR but not of alpha(1)D-AR. In agreement with the differential cell proliferation effect, cAMP production was increased after activation of alpha(1)A/alpha(1)B-AR but not alpha(1)D-AR, whereas all alpha(1)-AR subtypes are associated with inositol 1,4,5-trisphosphate production and mitogen-activated protein kinase activation in a similar fashion. Furthermore, the serum-induced reduction in the levels of the cyclin-dependent kinase inhibitor, p27(Kip1), was blocked after activation of alpha(1)A/alpha(1)B-AR but not alpha(1)D-AR. These results show that alpha(1)-AR subtypes differentially activate the cAMP/p27(Kip1) pathway and thereby have differential inhibitory effects on cell proliferation. Subtype-dependent effects should be taken into consideration when assessing the physiological response of native cells where alpha(1)-AR subtypes are generally co-expressed.
Shibata
Katsushi
K
Department of Molecular and Cell Pharmacology, National Center for Child Health and Development Research Institute, 3-35-31 Taishido, Setagaya-Ku, Tokyo 154-8567, Japan.
Katsuma
Susumu
S
Koshimizu
Takaaki
T
Shinoura
Hitomi
H
Hirasawa
Akira
A
Tanoue
Akito
A
Tsujimoto
Gozoh
G
D000818:Animals; D016466:CHO Cells; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D006224:Cricetinae; D003470:Culture Media; D000242:Cyclic AMP / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D005434:Flow Cytometry; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D003470:Culture Media; D020033:Protein Isoforms; D018340:Receptors, Adrenergic, alpha-1; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D018844:Cyclin-Dependent Kinases; D020928:Mitogen-Activated Protein Kinases