POU family

The POU family is a group of transcription factors with a highly conserved homeodomain. It plays a central role in embryogenesis and is highly expressed in the cells of the neural crest and the developing brain. 15 POU genes have been found in the human genome.

In contrast, the genomes of the model organisms Drosophila and Caenorhabditis elegans contain only five and four POU genes respectively. Nevertheless, these transcription factors regulate a large number of biological processes. This is possible through a broad spectrum of interactions with other transcription or cofactors. The interacting proteins can also come from the POU family or from other families, such as Pax or Sox.

The POU domain itself is a highly conserved DNA-binding structure that has defined this family of transcriptional regulators. It consists of an N-terminal POU-specific (POUS) domain of approximately 75 amino acids and a C-terminal POU homeo (POUH) domain of 60 amino acids, joined by a less conserved linker region of variable length. Both the POUS and POUH domains form helix-turn-helix (H-T-H) motifs using the second and third helices of the subdomain. The third helix (the second of the H-T-H motif) is the DNA recognition helix and is therefore responsible for contact with the DNA and confers binding specificity to the target DNA sequence. Six classes of POU proteins (POU1F to POU6F) have been described in mammals. Some POU factors show widespread expression (e.g. OCT1), while others are restricted to specific cell types (e.g. BRN2 in melanoma cells).

The contribution of POU proteins to tumorigenicity likely depends on either direct or downstream transcriptional targets. For example, the expression of BRN3b in breast cancer correlates with and directly regulates the expression of heat shock protein-27, a protein associated with increased proliferation, invasion and chemoresistance in this tumor type(Lee et al. 2005). In melanoma cell lines, abrogation of BRN2 expression leads to a slowdown in proliferation rates, matrigel invasion and loss of tumorigenesis (Goodall et al. 2008), although the transcriptional targets of BRN2, whose gene products mediate these processes, have not been fully investigated.

The only BRN2 targets identified in melanocytic cells are GADD45 and MITF. The promoter of the GADD45 gene is activated by BRN2 in response to UVB (Lefort et al. 2001). Others have reported similar actions mediated by OCT1, including expression of GADD45 in response to UV and DNA damage, but in cell types that do not express BRN2 (Jin et al. 2001).

In contrast to GADD45, BRN2 acts as a repressor of MITF expression in melanoma cells by binding directly to a region adjacent to the TATA box( Goodall et al. 2008). Importantly, although BRN2 and MITF can be co-expressed in melanoma cell lines, in melanoma tissue samples BRN2 and MITF appear to be restricted to different subsets of cells within the same tumor. It remains to be clarified whether the contribution of BRN2 to melanoma invasion is limited to the suppression of MITF or whether other target genes are also involved.

Thus, it appears that the effect of BRN2 on the MITF promoter is specific and most likely depends on the relative expression and activity of other transcription factors (and cofactors) that coordinately regulate MITF (Vance et al. 2004).

BRN2 has been shown to play a central role in the proliferation of melanoma cells. Examination of the expression of the cell cycle inhibitor p27/Kip1 and its inactivator Jab1 in a series of nevi and melanoma samples showed that during melanoma progression from melanocytes, there is a correlation between the decrease in p27 levels and the increase in Jab1 expression.

Considering the proliferation- and differentiation-promoting activity associated with higher MITF levels, the reciprocal expression of BRN2 and MITF in melanomas suggests that BRN2 may be involved in promoting a de-differentiated phenotype via suppression of MITF. This is consistent with the observed higher BRN2 levels in cultured human melanoblasts compared to melanocytes and with higher expression and DNA binding activity in non-pigmented melanoma cell lines compared to pigmented lines(Cook et al. 2005)

The acronym POU is derived from three transcription factors present in many living organisms:

• the letter P comes from the pituitary-specific transcription factor Pit-1 (=POU1F1),
• the O comes from the octamer transcription factors Oct-1 (=POU2F1) and Oct-2 (=POU2F2), where the octamer sequence is ATGCAAAT, and
• the letter U from the neural Unc-86 transcription factor of Caenorhabditis elegans

1. Cook AL et al (2005). Co-expression of SOX9 and SOX10 during melanocytic differentiation in vitro. Exp. Cell Res 308: 222-235.
2. Goodall J et al. (2008) Brn-2 represses microphthalmia-associated transcription factor expression and marks a distinct subpopulation of microphthalmia-associated transcription factor-negative melanoma cells. Cancer Res 68: 7788-7794.
3. Huang YT et al. (2005) The neuronal POU transcription factor Brn-2 interacts with Jab1, a gene involved in the onset of neurodegenerative diseases. Neurosci. Lett 382: 175-178.
4. Jin S et al. (2001) Transcription factors Oct-1 and NF-YA regulate the p53-independent induction of the GADD45 following DNA damage. Oncogene 20: 2683-2690.
5. Lee SA et al. (2005) Expression of the Brn-3b transcription factor correlates with expression of HSP-27 in breast cancer biopsies and is required for maximal activation of the HSP-27 promoter. Cancer Res 65; 3072-3080.
6. Lefort K et al. (2001). The specific activation of gadd45 following UVB radiation requires the POU family gene product N-oct3 in human melanoma cells. Oncogene 20: 7375-7385.
7. Vance KW et al. (2004) The transcription network regulating melanocyte development and melanoma. Pigment Cell Res 17: 318-325.