Huntington's disease (HD) is caused by an expansion of a polyglutamine tract in the huntingtin (htt) protein. The amino-terminal fragment of htt, httex1p, can localize to the nucleus and interact with transcription factors such as p53 and CREB-binding protein (CBP). This study shows that httex1p coaggregates with p53 in cell culture and interacts with it in vitro and in cell culture. Expanded httex1p represses transcription of p53-regulated promoters, including p21 and MDR-1. httex1p also interacts with CBP and mSin3a, and CBP localizes to neuronal intranuclear inclusions in a transgenic mouse model of HD. These findings suggest that expanded htt may cause aberrant transcriptional regulation through its interaction with cellular transcription factors, leading to neuronal dysfunction and cell death in HD. The study also shows that httex1p interacts with p53 and CBP in vitro, and that expanded httex1p represses transcription of p53-regulated genes. The results indicate that the proline-rich region of htt is involved in transcriptional repression, and that the interaction between htt and p53 may be important in the pathogenesis of HD. The study also suggests that the interaction between htt and CBP may contribute to the transcriptional repression observed in HD. The findings highlight the potential role of htt in transcriptional regulation and its involvement in the pathogenesis of HD.Huntington's disease (HD) is caused by an expansion of a polyglutamine tract in the huntingtin (htt) protein. The amino-terminal fragment of htt, httex1p, can localize to the nucleus and interact with transcription factors such as p53 and CREB-binding protein (CBP). This study shows that httex1p coaggregates with p53 in cell culture and interacts with it in vitro and in cell culture. Expanded httex1p represses transcription of p53-regulated promoters, including p21 and MDR-1. httex1p also interacts with CBP and mSin3a, and CBP localizes to neuronal intranuclear inclusions in a transgenic mouse model of HD. These findings suggest that expanded htt may cause aberrant transcriptional regulation through its interaction with cellular transcription factors, leading to neuronal dysfunction and cell death in HD. The study also shows that httex1p interacts with p53 and CBP in vitro, and that expanded httex1p represses transcription of p53-regulated genes. The results indicate that the proline-rich region of htt is involved in transcriptional repression, and that the interaction between htt and p53 may be important in the pathogenesis of HD. The study also suggests that the interaction between htt and CBP may contribute to the transcriptional repression observed in HD. The findings highlight the potential role of htt in transcriptional regulation and its involvement in the pathogenesis of HD.