Akt/protein kinase B promotes survival and hormone-independent proliferation of thyroid cells in the absence of dedifferentiating and transforming effects.
The Akt/protein kinase B serine/threonine kinase is a downstream effector of phosphoinositide 3-kinase (PI3K). Akt is an important component of mitogenic and antiapoptotic signaling pathways and is implicated in neoplastic transformation. Thyroid cells in culture retain a differentiated phenotype consisting of epithelial cell morphology and the expression of several tissue-specific genes. The survival and proliferation of these cells depend on thyrotropin and a mixture of five additional hormones that includes insulin. The regulation of proliferation and the expression of the thyroid differentiation program are intimately connected processes. As a result, oncogenes that induce hormone-independent proliferation invariably impair the expression of the thyroid-specific differentiation markers. Given that thyrotropin and insulin stimulate Akt activation in thyroid cells, we set out to determine the effects of Akt on thyroid cell proliferation, survival, and differentiation. To this end, we expressed constitutively active myristylated Akt (myrAkt) in PC Cl 3 thyroid cells. The myrAkt-expressing cells continued to proliferate, even in the absence of hormones, and they were resistant to programmed cell death induced by starvation. These effects were paralleled by the induction of the G1 cyclins D3 and E and by the inhibition of induction of the proapoptotic Fas, Fas ligand, and BAD genes in starved cells. However, in marked contrast with several other oncogenes, myrAkt did not interfere with the expression of thyroid differentiation functions. These results unveil the existence of an Akt-triggered thyroid cell pathway that modulates proliferation and survival without affecting the expression of the thyroid cell differentiated phenotype.
Centro di Endocrinologia ed Oncologia Spermentale del Consiglio Nazionale delle Ricerche, c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Naples, Italy.
G
G
De Vita
M T
MT
Berlingieri
R
R
Visconti
M D
MD
Castellone
G
G
Viglietto
G
G
Baldassarre
M
M
Zannini
A
A
Bellacosa
P N
PN
Tsichlis
A
A
Fusco
M
M
Santoro
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D056743:Cyclin D3; D016213:Cyclins / Q000378:metabolism; D053938:DNA Fragmentation; D018076:DNA, Complementary / Q000378:metabolism; D053222:Fas Ligand Protein; D020287:In Situ Nick-End Labeling; D008562:Membrane Glycoproteins / Q000378:metabolism; D010641:Phenotype; D010957:Plasmids; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction; D013961:Thyroid Gland / Q000166:cytology*; D014162:Transfection; D051025:bcl-Associated Death Protein; D019014:fas Receptor / Q000378:metabolism
C494821:Bad protein, rat; D002352:Carrier Proteins; C534698:Ccnd3 protein, rat; D056743:Cyclin D3; D016213:Cyclins; D018076:DNA, Complementary; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D051025:bcl-Associated Death Protein; D019014:fas Receptor; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt