MouseBRN-3family of POU transcription factors: a new aminoterminal domain is crucial for the oncogenic activity ofBRN-3A

Abstract

The class IV POU domain genes Brn-3a, -b and -c are differentially expressed during neural development and at least Brn-3a also in neuroectodermal tumors. In contrast to Brn-3b and Brn-3c, Brn-3a encodes two protein variants: Brn-3a(l) and Brn-3a(s). Brn-3a(s) lacks 84 aminoterminal residues but is otherwise identical to Brn-3a(l). Outside the well conserved carboxyterminal POU domains all three Brn-3 proteins (-a, -b and -c) diverge until the aminoterminal end where a new domain of about 100 amino acids is identified. This domain is conserved only between Brn-3 proteins and other class IV POU factors. Brn-3a(l) that contains the complete domain but not Brn-3a(s) that lacks 84 amino acids of it is able to tumorigenically transform primary fibroblasts. Brn-3b that lacks 40 amino acids of the new domain does itself not transform, but abolishes the oncogenic potential of Brn-3a(l) when transfected together. This demonstrates not only that Brn3-a(l) is a proto-oncogene and may well be causally involved in the generation of neuroectodermal tumors but also suggests that the intactness of the new aminoterminal domain described here is crucial for oncogenic activity. In addition, our data indicate that Brn-3b acts as an inhibitor of Brn-3a(l) activity.

Activation of CDK4 Gene Expression in Human Breast Cancer Cells by the Brn-3b POU Family Transcription Factor

“…21,22 A construct containing the isolated POU domain of Brn-3b was also able to activate the CDK4 promoter, indicating that, as in the related Brn-3a factor, [23][24][25] the POU domain can act as a transcriptional activation domain, as well as a DNA binding domain.…”

Brn-3a neuronal transcription factor functional expression in human prostate cancer

“…[22][23][24] For example, overexpression of Brn-3a[l] but not Brn-3a[s] was found to be oncogenic in primary rat embryonic fibroblasts, conferring upon them the capability for anchorage-independent cell growth. 19 Additonally, only Brn-3a[l], possessing both the POU homeodomain and an N-terminal activation domain, was found to regulate the promoters of BRCA1, a-internexin and Bcl-2 in neuroblastoma and breast cancer cells. [22][23][24] In the present study, we determined that overexpression of only Brn-3a[s] (and not Brn-3a[l]) had marked effects on growth.…”

“…Use of an alternative promoter in this intron gives rise to second, shorter isoforms of Brn-3a and Brn-3b but not Brn-3c. [19][20][21] The longer 43 kDa isoforms of Brn-3a and Brn-3b (Brn-3a [l] and Brn-3b [l]) contain an additional domain at the amino terminus absent in the shorter 33 kDa Brn-3a [s] and Brn-3b[s], which is required for the cell-specific regulation of target genes including a-internexin, BRCA1 and Bcl-2. [22][23][24] Thus, long and short isoforms can be functionally distinct.…”

The Brn-3b POU family transcription factor represses expression of the BRCA-1 anti-oncogene in breast cancer cells

“…The Brn-3a and Brn-3b expression vectors contain full length cDNA clones under the control of the moloney murine leukaemia virus promoter and have previously been described (Theil et al, 1993;Morris et al, 1994). The BRCA-1 promoter/reporter constructs contain 4 kilo-bases or 400 bases of upstream sequence containing the BRCA-1 a and b promoters cloned into the pGL2 luciferase vector.…”

“…Brn-3a, Brn-3b and Brn-3c are closely related members of the POU family which are encoded by di erent genes (Theil et al, 1993) and are expressed in distinct but overlapping patterns in the developing and adult nervous system (He et al, 1989;Gerrero et al, 1993;Lillycrop et al, 1992;Turner et al, 1994;Ninkina et al, 1993). In addition however, expression of Brn-3a and Brn-3b has also been detected in some non neuronal cells such as cervical epithelium (Lillycrop et al, 1992;Ndisang et al, 1998) and in the testis (Budhram-Mahadeo et al, submitted).…”