Signal-induced functions of the transcription factor TFII-I

Abstract

We have learned a great deal over the last several years about the molecular mechanisms that govern cell growth, cell division and cell death. Normal cells pass through cell cycle (growth) and divide in response to mitogenic signals that are transduced through their cognate cell surface receptors to the nucleus. Despite the fact that cellular growth and division are mechanistically distinct steps, they are usually coordinately regulated, which is critical for normal cellular proliferation. The precise mechanistic basis for this coordinated regulation is unclear. TFII-I is a unique, signal-induced multifunctional transcription factor that is activated upon a variety of signaling pathways and appears to participate in distinct phases of cell growth. For instance, TFII-I is required for growth factor-induced transcriptional activation of the c-fos gene, which is essential for cell cycle entry. Two alternatively spliced isoforms of TFII-I exhibit opposing but necessary functions for mitogen-induced transcriptional activation of c-fos. Besides transcriptional activation of the c-fos proto-oncogene and eventual entry into cell cycle, TFII-I also appears to have a role in later phases of the cell cycle and cell division. Here we discuss how a multitude of signaling inputs target TFII-I isoforms, which may exert their functions in distinct phases of the cell cycle and play a key role in the coordinated regulation of cellular proliferation.

Figure 1. Schematic structure of TFII-I isoforms

(A) Schematics of the four TFII-I isoforms and their respective amino acid lengths. LZ: leucine zipper; NLS: nuclear localization signal; BR: basic region/DNA binding domain; R1-R6: repeat domains; a, b: exons a (21 aa) and b (22 aa) encoded regions. (B) The region between R1 and R2 is expanded to show key regulatory features. Shown are the two Src auto phosphorylation sites: EDXDY at positons 244-248 and 273-277; D-box: MAPK interaction site between aa 282-293; and PPII: polyproline II domain, SH3 binding motif. The sequence of the D-box is also shown with most conserved residues boxed and highlighted in red.

Figure 2. Growth factor mediated gene regulation by TFII-I isoforms

In the absence of signaling, TFII-Iβ remains in the nucleus, bound to the c-fos promoter. Because it appears to repress c-fos transcription and preferentially interacts with HDAC and LSD1, we surmise that promoter bound TFII-Iβ is associated with these co-repressors. In contrast, the TFII-IΔ isoform remains in the cytoplasm in the absence of signaling where it interacts with p190 RhoGAP. Upon mitogenic signaling, TFII-IΔ under goes tyrosine phosphorylation, interacts with activated MAPK/Erk and translocates to the nucleus. Nuclear TFII-I has been shown to bind to the same site on the c-fos promoter. Given that it interacts with G-kinase and MAPK, it is likely that promoter bound TFII-IΔ remains associated with these kinases.

Figure 3. TFII-I isoforms may connect lipid metabolism to gene expression

Because both isoforms of TFII-I have been described to interact with PLC-γ, we propose that TFII-IΔ interacts with (soluble) PLC-γ in the cytoplasm to regulate TRPC-3 mediated Ca²⁺ entry, while TFII-Iβ interacts with PLC-γ in the nucleus. In addition, TFII-I also interacts with Btk in the cytoplasm. Because TFII-Iβ interacts with chromatin modifiers such as HDACs and LSD1 and PLC-γ has been shown to play a role in transcription, it is possible that TFII-Iβ might connect phopsholipid metabolism to signal-induced gene regulation. Given the signal-induced reverse translocation of TFII-I isoforms, such a process might also lead to alteration in subcellular PLC-γ.

Figure 4. Function of TFII-I in distinct phases of cell cycle via differential modification

TFII-I appears to play distinct roles in distinct phases of cell cycle and cell division. We conjecture that this is achieved via differential post-translational modification of TFII-I, which might result in different interactions with different factors. The modifications might include tyrosine and serine/threonine phosphorylation as well as sumoylation and ubiquitylation. The function of individual isoforms of TFII-I in this process is currently unknown.