Thyroid hormone-induced cell proliferation in GC cells is mediated by changes in G1 cyclin/cyclin-dependent kinase levels and activity.
The thyroid hormone, 3,3', 5-triiodo-L-thyronine (T3), is essential for growth and regulation of metabolic functions. The biological activities of T3 are mediated by its interaction with the thyroid hormone nuclear receptors (TRs). The mechanism by which TRs mediate cell growth is unknown. We found that T3 stimulated cell growth in GC cells by shortening the doubling time approximately 3-fold. Flow cytometric analysis indicated that the growth stimulatory effect was mainly due to shortening of G1 phase accompanied by increases in S and G2/M phases of the cell cycle. These changes correlated with T3-induced increases in messenger RNA and protein levels of two key regulators of G1 progression, cyclins D1 and E, as well as cdk2. Furthermore, the kinase activities associated with cyclin D1 and E were activated up to 4-fold by T3, which led to increased phosphorylation of the retinoblastoma protein (Rb), the driving force in G1 to S cell cycle progression. These results show for the first time that the growth promoting effect of T3 in GC cells is mediated, at least in part, by increases in cyclin/cdk activities and the phosphorylation state of Rb. The functional link of T3 to Rb has important implications for the understanding of the biology of normal and cancer cells.
Barrera-Hernandez
G
G
Laboratory of Molecular Biology, Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland 20892-4255, USA.
Park
K S
KS
Dace
A
A
Zhan
Q
Q
Cheng
S Y
SY
D000818:Animals; D042846:CDC2-CDC28 Kinases; D002455:Cell Division / Q000187:drug effects*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D056746:Cyclin G; D056766:Cyclin G1; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism*; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D010766:Phosphorylation; D010911:Pituitary Neoplasms / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D014284:Triiodothyronine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C534704:Ccng1 protein, rat; D019927:Cyclin E; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D014284:Triiodothyronine; D019938:Cyclin D1; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; C495903:Cdk4 protein, rat; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases