High mobility group protein HMGA1 inhibits retinoblastoma protein-mediated cellular G0 arrest.
Retinoblastoma protein (RB) acts as a tumor suppressor in many tissue types, by promoting cell arrest via E2F-mediated transcriptional repression. In addition to the aberrant forms of the RB gene found in different types of cancers, many viral oncoproteins including the simian virus 40 large T antigen target RB. However, cellular factors that inhibit RB function remain to be elucidated. Here, we report that RB interacts with the high mobility group protein A1 (HMGA1), a-non-histone architectural chromatin factor that is frequently overexpressed in cancer cells. HMGA1 binds the small pocket domain of RB, and competes with HDAC1. Subsequently, overexpression of HMGA1 abolishes the inhibitory effect of RB on E2F-activated transcription from the cyclin E promoter. Under serum starvation, T98G cells had been previously shown to be arrested in the G0 phase in an RB-mediated manner. The G0 phase was characterized by growth arrest and low levels of transcription, together with the hypophosphorylation of RB and the downregulation of HMGA1. In contrast, such serum-depleted G0 arrest was abrogated in T98G cells overexpressing HMGA1. The overexpressed HMGA1 was found to form complexes with cellular RB, suggesting that downregulation of HMGA1 is required for G0 arrest. There were no phenotypic changes in HMGA1-expressing T98G cells in the presence of serum, but the persistent expression of HMGA1 under serum starvation caused various nuclear abnormalities, which were similarly induced in T antigen-expressing T98G cells. Our present findings indicate that overexpression of HMGA1 disturbs RB-mediated cell arrest, suggesting a negative control of RB by HMGA1.
Ueda
Yasuaki
Y
Department of Regeneration Medicine, Institute of Molecular Embryology and Genetics, Kumamoto University 2-2-1 Honjo, Kumamoto 860-0811, Japan.
Watanabe
Sugiko
S
Tei
Shuchin
S
Saitoh
Noriko
N
Kuratsu
Jun-Ichi
J
Nakao
Mitsuyoshi
M
D000818:Animals; D003001:Cloning, Molecular; D017930:Genes, Reporter; D005822:Genetic Vectors; D005982:Glutathione Transferase / Q000235:genetics; D025741:HMGA1a Protein / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D010957:Plasmids; D016192:Resting Phase, Cell Cycle; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors*; D014162:Transfection
D016160:Retinoblastoma Protein; D025741:HMGA1a Protein; D005982:Glutathione Transferase