Pigmentation PAX‐ways: the role of Pax3 in melanogenesis, melanocyte stem cell maintenance, and disease

Kubic, Jennifer D.; Young, Kacey P.; Plummer, R.; Ludvik, Anton E.; Lang, Deborah

doi:10.1111/j.1755-148x.2008.00514.x

Cited by 126 publications

(122 citation statements)

References 172 publications

(290 reference statements)

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“…MITF-M is a critical regulator of proliferation and migration, and optimal activity of this protein leads to the most favorable rate of proliferation and migration in a particular molecular context (12,13). Phosphorylation has differential effects on BRN2 interactions with the various classes of binding element in the promoters of the PAX3 and MITF genes, and both of these genes are involved in the proliferation and migration of melanocytes; these observations provide clues to the mechanisms underlying the phenotypes observed (13,23,34,62).…”

mentioning

confidence: 99%

Phosphorylation of BRN2 Modulates Its Interaction with the Pax3 Promoter To Control Melanocyte Migration and Proliferation

Berlin

Denat

Steunou

et al. 2012

Molecular and Cellular Biology

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f MITF-M and PAX3 are proteins central to the establishment and transformation of the melanocyte lineage. They control various cellular mechanisms, including migration and proliferation. BRN2 is a POU domain transcription factor expressed in melanoma cell lines and is involved in proliferation and invasion, at least in part by regulating the expression of MITF-M and PAX3. The T361 and S362 residues of BRN2, both in the POU domain, are conserved throughout the POU protein family and are targets for phosphorylation, but their roles in vivo remain unknown. To examine the role of this phosphorylation, we generated mutant BRN2 in which these two residues were replaced with alanines (BRN2TS¡BRN2AA). When expressed in melanocytes in vitro or in the melanocyte lineage in transgenic mice, BRN2TS induced proliferation and repressed migration, whereas BRN2AA repressed both proliferation and migration. BRN2TS and BRN2AA bound and repressed the MITF-M promoter, whereas PAX3 transcription was induced by BRN2TS but repressed by BRN2AA. Expression of the BRN2AA transgene in a Mitf heterozygous background and in a Pax3 mutant background enhanced the coat color phenotype. Our findings show that melanocyte migration and proliferation are controlled both through the regulation of PAX3 by nonphosphorylated BRN2 and through the regulation of MITF-M by the overall BRN2 level. POU family transcription factors are expressed in a wide variety of cell types. They are involved in diverse functions, such as cell type determination, proliferation, renewal, invasion, and migration. The members of the POU domain family of transcription factors share the POU DNA-binding domain (DBD) called the POU domain. The POU domain consists of two DNA-binding units (POUs for POU specific and POUh for POU homeodomain) connected by a flexible linker (3). This molecular structure allows POU proteins to recognize a large set of DNA targets and also to bind different transactivator proteins, depending on the spacing and the positioning adopted by the two subdomains of the POU DBD (50).POU transcription factor function can be modulated by posttranslational modifications, including sumoylation, oxidation, ubiquitinylation, glycosylation, and particularly phosphorylation (5,20,32). Two residues in the DBD domain, a threonine and a serine, are conserved in all mammalian POU domains (see Table S1 at http://umr3347.curie.fr/fr/quipes-de -recherche/d-veloppement-normal-et-pathologie-des-m-lanocytes /differential-function-non-pho). These serine and/or threonine residues in Oct-1, Pit-1, and BRN2 are phosphorylated by protein kinase A (PKA) (31,46,55).Several lines of evidence suggest that PKA is involved in melanocyte lineage proliferation. Forskolin stimulates the proliferation of human melanocytes (54). Proliferation of human melanocytes is induced in a dose-dependent manner by alphamelanocyte-stimulating hormone (1,57,58). Dibutyryl adenosine cyclic AMP induces the proliferation of epidermal melanocytes in culture (29). PKA phosphorylates claudin-1 and allows its tr...

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mentioning

confidence: 99%

Phosphorylation of BRN2 Modulates Its Interaction with the Pax3 Promoter To Control Melanocyte Migration and Proliferation

Berlin

Denat

Steunou

et al. 2012

Molecular and Cellular Biology

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“…Being an important developmental factor, the expression of PAX3 gradually decreases as the tissues differentiate. However, its reexpression in differentiated adult tissues that require PAX3 function during embryonic development leads to several tumors [3,15].…”

Section: Introductionmentioning

confidence: 99%

“…PAX3 contains all three complete structural domains: a paired domain, homeodomain, and octopeptide, which is a characteristic of PAX family of proteins. PAX3 interacts with other transcription factors through its paired domain (PD) and recruits them to target promoters [14,15]. PAX3 is expressed as several isoforms such as PAX3a, PAX3b, PAX3c, PAX3d, PAX3e, PAX3g, and PAX3h [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

PAX3: A Molecule with Oncogenic or Tumor Suppressor Function Is Involved in Cancer

Arasu

Murugan

Essa

et al. 2018

BioMed Research International

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Metastasis is the most deadly aspect of cancer and results from acquired gene regulation abnormalities in tumor cells. Transcriptional regulation is an essential component of controlling of gene function and its failure could contribute to tumor progression and metastasis. During cancer progression, deregulation of oncogenic or tumor suppressive transcription factors, as well as master cell fate regulators, collectively influences multiple steps of the metastasis cascade, including local invasion and dissemination of the tumor to distant organs. Transcription factor PAX3/Pax3, which contributes to diverse cell lineages during embryonic development, plays a major role in tumorigenesis. Mutations in this gene can cause neurodevelopmental disease and the existing literature supports that there is a potential link between aberrant expression of PAX3 genes in adult tissues and a wide variety of cancers. PAX3 function is tissue-specific and could contribute to tumorigenesis either directly as oncogene or as a tumor suppressor by losing its function. In this review, we discuss comprehensively the differential role played by PAX3 in various tissues and how its aberrant expression is implicated in disease development. This review particularly highlights the oncogenic and tumor suppressor role played by PAX3 in different cancers and underlines the importance of precisely identifying tissue-specific role of PAX3 in order to determine its exact role in development of cancer.

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“…In part, the impact of Pax3 in development arises through its ability to promote expression of MITF, and Pax3-deficient mice exhibit pigmentation defects as a result (31). In addition, Pax3 can also block terminal differentiation (32), a mechanism that also may contribute to the uncontrolled cell growth and loss of terminal differentiation in melanomas where Pax3 is commonly expressed (37,43).…”

Section: Discussionmentioning

confidence: 99%

A Phosphatidylinositol 3-Kinase–Pax3 Axis Regulates Brn-2 Expression in Melanoma

Bonvin

Falletta

Shaw

et al. 2012

Molecular and Cellular Biology

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bDeregulation of transcription arising from mutations in key signaling pathways is a hallmark of cancer. In melanoma, the most aggressive and lethal form of skin cancer, the Brn-2 transcription factor (POU3F2) regulates proliferation and invasiveness and lies downstream from mitogen-activated protein kinase (MAPK) and Wnt/␤-catenin, two melanoma-associated signaling pathways. In vivo Brn-2 represses expression of the microphthalmia-associated transcription factor, MITF, to drive cells to a more stem cell-like and invasive phenotype. Given the key role of Brn-2 in regulating melanoma biology, understanding the signaling pathways that drive Brn-2 expression is an important issue. Here, we show that inhibition of phosphatidylinositol 3-kinase (PI3K) signaling reduces invasiveness of melanoma cells in culture and strongly inhibits Brn-2 expression. Pax3, a transcription factor regulating melanocyte lineage-specific genes, directly binds and regulates the Brn-2 promoter, and Pax3 expression is also decreased upon PI3K inhibition. Collectively, our results highlight a crucial role for PI3K in regulating Brn-2 and Pax3 expression, reveal a mechanism by which PI3K can regulate invasiveness, and imply that PI3K signaling is a key determinant of melanoma subpopulation diversity. Together with our previous work, the results presented here now place Brn-2 downstream of three melanoma-associated signaling pathways.

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Pigmentation PAX‐ways: the role of Pax3 in melanogenesis, melanocyte stem cell maintenance, and disease

Cited by 126 publications

References 172 publications

Phosphorylation of BRN2 Modulates Its Interaction with the Pax3 Promoter To Control Melanocyte Migration and Proliferation

Phosphorylation of BRN2 Modulates Its Interaction with the Pax3 Promoter To Control Melanocyte Migration and Proliferation

PAX3: A Molecule with Oncogenic or Tumor Suppressor Function Is Involved in Cancer

A Phosphatidylinositol 3-Kinase–Pax3 Axis Regulates Brn-2 Expression in Melanoma

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