C-terminal activating and inhibitory domains determine the transactivation potential of BSAP (Pax-5), Pax-2 and Pax-8.

Dörfler, P; Busslinger, Meinrad

doi:10.1002/j.1460-2075.1996.tb00548.x

Cited by 140 publications

(154 citation statements)

References 50 publications

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“…Carboxyl inhibitory or masking domains are common regulatory motifs observed in a number of transcription factors including PHO4, c-Myb, Pax2, Pax5, Pax8, C/EBP␤(NF-M), Nkx2.5, and Pitx2 (11,(41)(42)(43)(44)(45). The mechanism of action for these inhibitory domains varies depending on the transcription factor examined.…”

Section: Discussionmentioning

confidence: 99%

The Identification of Prx1 Transcription Regulatory Domains Provides a Mechanism for Unequal Compensation by thePrx1 and Prx2 Loci

Norris

Kern

2001

Journal of Biological Chemistry

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Transcription regulatory domains of the Prx1a and Prx1b homeoproteins were analyzed in transient transfection assays using artificial promoters as well as an established downstream target promoter (tenascin-c). Activation and repression domains were detected in their common amino end. In the carboxyl end of Prx1a an activation domain and an inhibition/masking region (OAR domain) were detected. The Prx1b isoform, generated by alternative splicing, does not contain these carboxyl activation or inhibition domains. Instead, the data demonstrate that the carboxyl tail of Prx1b contains a potent repressor region. This difference in the carboxyl tail accounts for a 45-fold difference observed in transcription regulatory activity between Prx1a and Prx1b. The data also support the likelihood that this difference between Prx1a and Prx1b is higher in the presence of still undetermined cofactors. DNA binding affinities of Prx1a, Prx1b, and a series of truncation mutants were also examined. The carboxyl tail of Prx1a, which inhibited transcription activation in the transfection assays, also inhibited DNA binding. These differences in biochemical function between Prx1a and Prx1b, as well as the recently described activities of Prx2, provide a mechanism for the unequal compensation between the Prx1 and Prx2 loci.Paired type homeobox transcription factors are important regulators of morphogenetic processes and have been conserved in a diverse selection of species. The Prx1 and Prx2 genes are members of this class and thus encode proteins that contain a paired type DNA binding homeodomain but lack a second DNA binding domain (i.e. the paired domain) present in other paired related homeoproteins (1, 2). Prx1 (also known as mhox, k2, Pmx, PRRX1) (3-6) and Prx2 (also known as S8 and PRRX2) (6 -8) are 97% identical within their homeodomains and 64% identical over the entire molecule. This high degree of sequence homology as well as similar expression and genomic organization suggest that Prx1 and Prx2 are the result of a gene duplication event (3-6, 8 -10).Despite many similarities, important differences in splicing of Prx1 and Prx2 are evident. Alternative splicing of Prx1

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Section: Discussionmentioning

confidence: 99%

The Identification of Prx1 Transcription Regulatory Domains Provides a Mechanism for Unequal Compensation by thePrx1 and Prx2 Loci

Norris

Kern

2001

Journal of Biological Chemistry

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“…Studies on the Pax8 transcriptional properties showed that the C terminus of Pax8a is required for transactivation (26). In particular, the data obtained studying various Pax genes showed that the regulatory module of these proteins consisting of a potent transactivation region has been conserved among the members of the family and lies in the C-terminal region downstream amino acid 300 (26).…”

Section: Pax8 Splicing Isoforms Are Able To Reactivate Endogenous Tg mentioning

confidence: 99%

“…In particular, the data obtained studying various Pax genes showed that the regulatory module of these proteins consisting of a potent transactivation region has been conserved among the members of the family and lies in the C-terminal region downstream amino acid 300 (26). Thus the C-terminal region of Pax8, as well as that of other Pax genes, represents the only domain of the protein involved in transcriptional activation that has been identified so far.…”

Section: Pax8 Splicing Isoforms Are Able To Reactivate Endogenous Tg mentioning

confidence: 99%

Pax8 has a key role in thyroid cell differentiation

Magliano

Lauro

Zannini

2000

Proc. Natl. Acad. Sci. U.S.A.

222

132

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Transformation of rat thyroid cells with polyoma virus middle T antigen results in loss of the thyroid-differentiated phenotype, measured as the expression of the thyroglobulin (Tg), thyroperoxidase (TPO), and sodium͞iodide symporter (NIS) genes. Among the transcription factors involved in the regulation of these genes, TTF-1 and TTF-2 were still detected at nearly wild-type levels, while a specific loss of the paired domain transcription factor Pax8 was observed. In this study, we used the PCPy cell line as a model system to study the role of Pax8 in thyroid differentiation. We demonstrate that the reintroduction of Pax8 in PCPy cells is sufficient to activate expression of the endogenous genes encoding thyroglobulin, thyroperoxidase, and sodium͞iodide symporter. Thus, this cell system provides direct evidence for the ability of Pax8 to activate transcription of thyroid-specific genes at their chromosomal locus and strongly suggests a fundamental role of this transcription factor in the maintenance of functional differentiation in thyroid cells. Moreover, we show that Pax8 and TTF-1 cooperate in the activation of the thyroglobulin promoter and that additional thyroid-specific mechanism(s) are involved in such a cooperation. To identify the Pax8 domain able to mediate the specific activation of the thyroglobulin promoter, we transfected in PCPy cells three different Pax8 isoforms. The results of such experiments indicate that for the transcriptional activation of thyroid-specific genes, Pax8 uses an as yet unidentified functional domain.Pax genes ͉ gene expression T erminally differentiated cells express genes whose products are undetectable in other cell types. The isolation of regulatory DNA sequences responsible for such cell-type-specific expression and the cloning of the cDNAs encoding cognate transcription factors revealed, in the majority of cases, that a combination of transcription factors is unique to a cell type. Thus, transcription of cell-type-specific genes appears to depend on synergy between transcription factors (1, 2). Frequently, transcription factors controlling the expression of genes specific to the terminal differentiation state of a given cell type play an additional role earlier in the development of the same cell type. As a consequence, the identification of factors controlling cell-type-specific gene expression also provides relevant information on earlier developmental stages in many organs and cell lineages. However, a direct assessment of the role of many transcription factors in cell-type-specific gene expression has proven difficult, given that mice lacking the relevant transcription factors often show complete absence of the implicated cell type.To elucidate the mechanism(s) operating in the establishment and maintenance of cell-type-specific expression, we have been studying a model system represented by the thyroid follicular cells, the most abundant cell population of the thyroid gland. These cells are responsible for thyroid hormone synthesis and are characterized by the expr...

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“…Among them is the B-cellspecific activator protein (BSAP), which is encoded by the Pax5 gene . This transcription factor is expressed at all stages of B lymphopoiesis except in terminally differentiated plasma cells (Barberis et al 1990), recognizes DNA via its amino-terminal paired do main (Czerny et al 1993), and uses a carboxy-terminal regulatory module consisting of activating and inhibi tory sequences to control gene transcription (Dorfler and Busslinger 1996). BSAP (Pax5) has been implicated in the regulation of several B-cell-specific genes primarily based on the identification of BSAP-binding sites in their control regions.…”

mentioning

confidence: 99%

Essential functions of Pax5 (BSAP) in pro-B cell development: difference between fetal and adult B lymphopoiesis and reduced V-to-DJ recombination at the IgH locus.

Nutt¹,

Urbánek²,

Rolink³

et al. 1997

Genes Dev.

379

377

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C-terminal activating and inhibitory domains determine the transactivation potential of BSAP (Pax-5), Pax-2 and Pax-8.

Cited by 140 publications

References 50 publications

The Identification of Prx1 Transcription Regulatory Domains Provides a Mechanism for Unequal Compensation by thePrx1 and Prx2 Loci

The Identification of Prx1 Transcription Regulatory Domains Provides a Mechanism for Unequal Compensation by thePrx1 and Prx2 Loci

Pax8 has a key role in thyroid cell differentiation

Essential functions of Pax5 (BSAP) in pro-B cell development: difference between fetal and adult B lymphopoiesis and reduced V-to-DJ recombination at the IgH locus.

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