HMGA1 inhibits the function of p53 family members in thyroid cancer cells.
HMGA1 is an architectural transcription factor expressed at high levels in transformed cells and tumors. Several lines of evidence indicate that HMGA1 up-regulation is involved in the malignant transformation of thyroid epithelial cells. However, the mechanisms underlying the effect of HMGA1 on thyroid cancer cell phenotype are not fully understood. We now show that in thyroid cancer cells, HMGA1 down-regulation by small interfering RNA and antisense techniques results in enhanced transcriptional activity of p53, TAp63alpha, TAp73alpha, and, consequently, increased apoptosis. Coimmunoprecipitation and pull-down experiments with deletion mutants showed that the COOH-terminal oligomerization domain of p53 family members is required for direct interaction with HMGA1. Moreover, inhibition of HMGA1 expression in thyroid cancer cells resulted in increased p53 oligomerization in response to the DNA-damaging agent doxorubicin. Finally, electrophoretic mobility shift assay experiments showed that the p53-HMGA1 interaction results in reduced DNA-binding activity. These results indicate a new function of HMGA1 in the regulation of p53 family members, thus providing new mechanistic insights in tumor progression.
Frasca
Francesco
F
Endocrinologia, Dipartimento di Medicina Interna, e Medicina Specialistica, Ospedale Garibaldi, Catania, Italy.
Rustighi
Alessandra
A
Malaguarnera
Roberta
R
Altamura
Sandro
S
Vigneri
Paolo
P
Del Sal
Giannino
G
Giancotti
Vincenzo
V
Pezzino
Vincenzo
V
Vigneri
Riccardo
R
Manfioletti
Guidalberto
G
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004273:DNA, Neoplasm / Q000378:metabolism; D025741:HMGA1a Protein / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D004273:DNA, Neoplasm; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025741:HMGA1a Protein