Understanding PLZF

Abstract

PLZF can function as a transcriptional activator or as a transcriptional repressor. Recent studies have identified two direct transcriptional targets of PLZF, REDD1 and smooth muscle α-actin. REDD1 is activated by PLZF. It mediates the PLZF-dependent downregulation of TORC1 and is responsible for the maintenance of pluripotency in cultures of spermatogonial progenitor cells. This activity may extend to other stem-like cell types. The effect of REDD1 on TORC1 also raises the possibility that REDD1 controls cell growth, tumorigenicity and senescence. The regulatory loop extending from PLZF via REDD1 to TORC1 identifies REDD1 as a critical determinant of TOR activity. The transcription of smooth muscle α-actin is repressed by PLZF. In fibroblasts, this downregulation is accompanied by a change of cell shape and a dramatic reorganization of the cytoskeleton. It is also correlated with the acquisition of cellular resistance to oncogenic transformation. The resistance is selective, it works against some oncoproteins but not against others. The molecular mechanisms underlying the changes in the cytoskeleton and in the susceptibility to oncogenic transformation are unknown. However these changes are dependent on the activity of RAS and thus probably involve the RAC/RHO family of proteins.

Acknowledgements

Work of the authors is supported by NIH grants R01 CA078230 and P01 CA078045. This is manuscript 21044 of The Scripps Research Institute.

Figures and Tables

Figure 1 In spermatogonial progenitor cells from PLZF^+/+ mice, PLZF activates the transcription of REDD1, leading to an attenuation of TORC1 activity. The negative feedback activity from TORC1 is reduced allowing effective signaling from GCNF and other growth factors. Such signals are essential for allowing self-renewal of pluripotent cells. In spermatogonial progenitors from PLZF^−/− mice, hyperactive TORC1 generates negative feedback interfering with signals from growth factors that are essential for the maintenance of pluripotency.

Figure 2 Overexpression of PLZF induces a profound reorganization of the cytoskeleton in fibroblasts, accompanied by a change in cell shape from elongated to polygonal. The PLZF-expressing cells show resistance to the transforming activity of several oncoproteins.

Figure 3 Summary of PLZF functions that are mediated through the transcriptional regulation of REDD1 and of α-actin.

Table 1 Direct Target Genes of PLZF1