Phosphoinositide 3-kinase/AKT Signaling Can Promote AIB1 Stability Independently of GSK3 Phosphorylation

• Published in: Cancer research (Chicago, Ill.) Vol. 68; no. 13; pp. 5450 - 5459
• Main Authors: FERRERO, Macarena, AVIVAR, Alvaro, GARCIA-MACIAS, Maria Carmen, DE MORA, Jaime Font
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.07.2008
• Subjects: Active Transport, Cell Nucleus - drug effects; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Cell Nucleus - metabolism; Glycogen Synthase Kinase 3 - metabolism; HeLa Cells; Humans; Leupeptins - pharmacology; Medical sciences; Models, Biological; Nuclear Receptor Coactivator 3; Oncogene Protein v-akt - metabolism; Oncogene Protein v-akt - physiology; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositol 3-Kinases - physiology; Phosphorylation; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors; Protein Processing, Post-Translational - drug effects; Protein Structure, Tertiary - physiology; Signal Transduction - physiology; Tissue Distribution; Transcription Factors - chemistry; Transcription Factors - metabolism; Tumors; Ubiquitination - physiology; Signal transduction; Phosphorylation; Stability; Enzyme; Transferases; C-Onc gene; Akt protein kinase; Physicochemical properties; Protooncogene; 1-Phosphatidylinositol 3-kinase
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-07-6433

The transcriptional coactivator AIB1 is an oncogene overexpressed in different types of tumors, including breast cancer. Although the subcellular compartimentalization of AIB1 seems to be intimately linked to abnormal proliferation, the molecular mechanisms that regulate its subcellular distribution are not well defined. Here, we report that the nuclear accumulation and half-life of AIB1 vary between cancer cell lines. Using these differences as an experimental model, our results reveal that alterations to the Akt signaling pathway and nuclear export determine the stability of AIB1 and nuclear content of this coactivator. Moreover, our results show that AIB1 is degraded in the nucleus by the proteasome in an ubiquitin-dependent manner. However, this process does not require phosphorylation by GSK3, thereby revealing an alternative mechanism for regulating the turnover of AIB1. We define a new region at the carboxy terminus of AIB1 that is required for proteasome-dependent transcriptional activation and is preceded by a PEST domain that is required for adequate protein turnover. Based on differences in Akt signaling and the subcellular distribution of AIB1 between different cell lines, our results suggest that dysregulation of nuclear shuttling and proteasomal degradation may modulate the oncogenic potential of AIB1.