Biochemistry and biology of the inducible multifunctional transcription factor TFII-I: 10 years later

Abstract

Exactly twenty years ago TFII-I was discovered as a biochemical entity that was able to bind to and function via a core promoter element called the Initiator (Inr). Since then several different properties of this signal-induced multifunctional factor were discovered. Here I update these ever expanding functions of TFII-I--focusing primarily on the last ten years since the first review appeared in this journal.

Figure 1. Structural Features of TFII-I

a) Schematic of TFII-I with 6 repeated regions, R1–R6, the N-terminal leucine zipper (LZ) and the basic region (BR) which serves as a DNA binding domain. B) The sequence of the repeats R1–R6. The most conserved amino acids are indicated in bold and the I-repeat is underlined. c) Both the linear arrangement and NMR structure of the murine repeat 5 (R5). The various amphipathic helices are indicated as α1–4 and the beta sheets are indicated as β1 and β2. The figure depicting the NMR structure is kindly provided by H. Hirota. This unique structural fold is referred to as an I-fold.

Figure 2. Schematic of the TFII-I family transcription factors

TFII-I, also known as GTF2I has 6 repeats (R1–R6) with the NLS and BR preceding R2. BEN (GTF2IRD1/MusTRD1/GTF3) has five repeats with the NLS located toward the C-terminal region. The S-S is a serine stretch, the precise function of which is unknown. The third member, GTF2IRD2 has only two repeats (R1 and R2) and does not have any NLS. The N-terminal region of this member shares 75% identity with TFII-I and resembles a truncated TFII-I. GTF2IRD2 has a Charlie8 transposon-like domain. However, the function of this domain is currently unknown. The N-terminal leucine zipper (LZ) is well conserved amongst the three members.

Figure 3. Growth factor signal induced regulation of transcription by the two isoforms of TFII-I

(A) In basal state, unphosphorylated TFII-IΔ is predominantly cytoplasmic, tethered by p190RhoGAP (p190). Other molecules can also tether TFII-I in the cytoplasm (not shown for simplicity). TFII-Iβ is recruited to a c-fos promoter site, likely in conjunction with co-repressors (red) (e.g., HDAC1 and 3, LSD1 or PRC) resulting in a transcriptional repression. (B) Upon signaling, TFII-IΔ undergoes phosphorylation, interacts with Erk1/2 and translocate to the nucleus. Under these conditions, TFII-Iβ is exported out of the nucleus and instead TFII-IΔ occupies the same site on the c-fos promoter, resulting in transcriptional activation. It is conjectured that under these conditions, TFII-IΔ interacts with transcriptional co-activators (green), although the precise identities of these factors are currently unknown.

Figure 4. Signal dependent activation and repression mediated by TFII-I

Shown on the left, signal -dependent transcriptional repression mediated by TFII-I (in red). The target genes and functional consequences are indicated. Shown on the right, signal-dependent transcriptional activation mediated by TFII-I (in green). These functions are likely to be signal and cell type dependent as activation and repression of both VEGFR2 and cyclin D1 have been shown.

Figure 5. Interacting partners of TFII-I

The interacting proteins are divided into four functional groups: transcription factors/co-factors, chromatin modifying factors, histone modifying factors and signaling molecules. These interactions are observed in different cell types and under distinct conditions.