title: The human papillomavirus type 11 and 16 E6 proteins modulate the cell-cycle regulator and transcription cofactor TRIP-Br1.
abstract: The genital human papillomaviruses (HPVs) are a taxonomic group including HPV types that preferentially cause genital and laryngeal warts ("low-risk types"), such as HPV-6 and HPV-11, or cancer of the cervix and its precursor lesions ("high-risk types"), such as HPV-16. The transforming processes induced by these viruses depend on the proteins E5, E6, and E7. Among these oncoproteins, the E6 protein stands out because it supports a particularly large number of functions and interactions with cellular proteins, some of which are specific for the carcinogenic HPVs, while others are shared among low- and high-risk HPVs. Here we report yeast two-hybrid screens with HPV-6 and -11 E6 proteins that identified TRIP-Br1 as a novel cellular target. TRIP-Br1 was recently detected by two research groups, which described two separate functions, namely that of a transcriptional integrator of the E2F1/DP1/RB cell-cycle regulatory pathway (and then named TRIP-Br1), and that of an antagonist of the cyclin-dependent kinase suppression of p16INK4a (and then named p34SEI-1). We observed that TRIP-Br1 interacts with low- and high-risk HPV E6 proteins in yeast, in vitro and in mammalian cell cultures. Transcription activation of a complex consisting of E2F1, DP1, and TRIP-Br1 was efficiently stimulated by both E6 proteins. TRIP-Br1 has an LLG E6 interaction motif, which contributed to the binding of E6 proteins. Apparently, E6 does not promote degradation of TRIP-Br1. Our observations imply that the cell-cycle promoting transcription factor E2F1/DP1 is dually targeted by HPV oncoproteins, namely (i) by interference of the E7 protein with repression by RB, and (ii) by the transcriptional cofactor function of the E6 protein. Our data reveal the natural context of the transcription activator function of E6, which has been predicted without knowledge of the E2F1/DP1/TRIP-Br/E6 complex by studying chimeric constructs, and add a function to the limited number of transforming properties shared by low- and high-risk HPVs.
authors.affiliation: Institute of Molecular and Cell Biology, 30 Medical Drive, Singapore 117609.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gupta
authors.forename: Param Parkash S
authors.initials: PP
authors.lastname: Takhar
authors.forename: Roland
authors.initials: R
authors.lastname: Degenkolbe
authors.forename: Choon Heng
authors.initials: CH
authors.lastname: Koh
authors.forename: Holger
authors.initials: H
authors.lastname: Zimmermann
authors.forename: Christopher Maolin
authors.initials: CM
authors.lastname: Yang
authors.forename: Khe
authors.initials: K
authors.lastname: Guan Sim
authors.forename: Stephen I-Hong
authors.initials: SI
authors.lastname: Hsu
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Bernard
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D012097:Repressor Proteins; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D020798:Two-Hybrid System Techniques
chemical_list: C469553:E6 protein, Human papillomavirus type 11; C068651:E6 protein, Human papillomavirus type 16; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; C402464:SERTAD1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors