Human papillomaviruses (HPVs) are small, doublestranded DNA viruses that infect squamous epithelial cells and have been strongly implicated in the development of human cervical cancer, which is the second most common cancer worldwide and the leading cause of death from cancer among women in developing countries (32,35,52). HPV E2 is a ϳ40-kDa nuclear protein that binds DNA and is a prototypical transcription factor with an N-terminal transcriptional activation domain (TAD) and a C-terminal DNA binding domain (DBD) separated by a hinge region (HR) (11). The E2 protein is an important regulator of elements of the viral life cycle such as viral transcription, viral DNA replication, and viral genome maintenance (11,30,31). To regulate viral transcription, HPV E2 can serve as either activator or repressor of transcription, depending upon the context of E2 binding sites within the promoter region. There are four E2 binding sites within the HPV long control region (LCR). The binding of E2 to the promoter-distal sites within the LCR could activate HPV transcription. When HPV E2 protein binds to the promoter-proximal sites, it functions as a transcription repressor (42) by preventing Sp1 and TFIID/TBP from binding to their cognate sequences, thereby inhibiting assembly of the transcription initiation complex.It is inconceivable that E2 can achieve its multiple functions without interacting with other proteins, and several E2-interaction proteins have already been reported. The TAD of E2 interacts with numerous viral and cellular proteins, including viral E1 protein, TFIIB, CHIR1, Brd4, NAP-1, p300/CBP, p/CAF, GR, and Tax1BP1 (23,26,29,33,39,46,47,49). Previous studies have reported that E2 proteins exhibit short half-lives due to degradation by the ubiquitin/proteasome pathway (3, 38). The TAD of E2 protein is highly conserved between papillomavirus groups and widely reported to be essential for ubiquitination and degradation by the proteasome. The C-terminal domain of E2 (such as BPV E2R) has a longer half-life due to the fact that it is not a good substrate for the ubiquitin-proteasome machinery (15). Several recently reported E2 interacting proteins bind to the TAD of E2 and contribute to E2 protein stability, such as Brd4 (8, 24, 51), Skp2 (4), and Tax1BP1 (46), but the mechanisms are still unclear. Moreover, mutational analysis in vitro has shown that the phosphorylation of BPV-1 E2 shortens the half-life of the protein (37) although the detailed mechanism of how E2 phosphorylation leads to protein degradation remains unclear.We previously identified a novel gene and named the protein nuclear receptor interaction protein (NRIP) (GenBank accession numbers AY766164 and AAX09330). The NRIP protein is composed of 860 amino acids and seven WD40 domains (43). NRIP acts to upregulate androgen receptor (AR) and glucocorticoid receptor (GR)-driven transcriptional activity of the native mouse mammary tumor virus (MMTV) promoter. Knockdown of NRIP expression can decrease the growth rate of various cells, implying that NRIP mig...