Continuous expression of the homeobox gene Pax6 in the ageing human retina

Stanescu, Diana E.; Iseli, Hans Peter; Kerstin, Schwerdtfeger; Ittner, Lars M.; Remé, Ch.; Hafezi, Farhad

doi:10.1038/sj.eye.6702166

Cited by 33 publications

(37 citation statements)

References 17 publications

(28 reference statements)

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“…We indeed detected Pax6 in the inner nuclear layer of human retina (Fig. 3B, left), in agreement with previous reports (58). However, we did not detect Pax6(S) in retina (Fig.…”

Section: A) Indicating That the Novel S Tail Of Pax6(s) Does Not Chsupporting

confidence: 93%

The β Subunit of Voltage-gated Ca2+ Channels Interacts with and Regulates the Activity of a Novel Isoform of Pax6

Zhang¹,

Yamada²,

Fan

et al. 2010

Journal of Biological Chemistry

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Ca2؉ channel ␤ subunits (Ca v ␤s) are essential for regulating the surface expression and gating of high voltage-activated Ca 2؉ channels through their interaction with Ca 2؉ channel ␣ 1 subunits. In efforts to uncover new interacting partners and new functions for Ca v ␤, we identified a new splicing isoform of Pax6, a transcription factor crucial for the development of the eye, nose, brain, and pancreas. Pax6 contains two DNA binding domains (paired domain and homeodomain), a glycine-rich linker connecting these two domains and a C-terminal proline-, serine-, and threonine-rich transactivation domain. The protein sequence and function of Pax6 are highly conserved from invertebrate to human. The newly isolated isoform, named Pax6(S), retains the paired domain, linker, and homeodomain of Pax6, but its C terminus is composed of a truncated classic proline, serine, and threonine domain and a unique S tail. Pax6(S) shows a similar level of transcriptional activity in vitro as does Pax6, but only in primates is the protein sequence highly conserved. Its spatial-temporal expression profiles are also different from those of Pax6. These divergences suggest a noncanonical role of Pax6(S) during development. The interaction between Pax6(S) and Ca v ␤ is mainly endowed by the S tail. Co-expression of Pax6(S) with a Ca 2؉ channel complex containing the ␤ 3 subunit in Xenopus oocytes does not affect channel properties. Conversely, however, ␤ 3 is able to suppress the transcriptional activity of Pax6(S). Furthermore, in the presence of Pax6(S), ␤ 3 is translocated from the cytoplasm to the nucleus. These results suggest that full-length Ca v ␤ may act directly as a transcription regulator independent of its role in regulating Ca 2؉ channel activity.4 is a cytosolic auxiliary protein of multimeric high voltage-activated (HVA) Ca 2ϩ channel complexes, which include L-, N-, P/Q-, and R-type Ca 2ϩ channels. It plays an essential role in chaperoning the channel complex to the plasma membrane and normalizing its gating properties (1-4). Crystal structures of Ca v ␤ in complex with its high affinity binding site in the principal poreforming ␣ 1 subunit (Ca v ␣ 1 ) show that much of the exposed surface of Ca v ␤ is unoccupied and is available to engage in interactions with other regions of Ca v ␣ 1 or with other proteins (5-7). Indeed, an increasing number of proteins has been shown to directly interact with Ca v ␤, including the Rem/Rad/Gem/Kir (RGK) family of small monomeric GTPases (8, 9), RIM1 (10), ryanodine receptors (11), Ahnak (12, 13), bestrophin-1 (14), and dynamin (15). Many of these proteins have been reported to regulate the activity of HVA Ca 2ϩ channels. To search for other potential Ca v ␤-interacting proteins, we carried out yeast two-hybrid screens using the ␤ 3 subunit as bait. Among the candidate target proteins we isolated, one was related to Pax6.Pax6 is a transcription factor that belongs to the paired box (Pax) family (16 -25). It is widely expressed in the eye, nose, pancreas, and the central nervous system ...

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“…We indeed detected Pax6 in the inner nuclear layer of human retina (Fig. 3B, left), in agreement with previous reports (58). However, we did not detect Pax6(S) in retina (Fig.…”

Section: A) Indicating That the Novel S Tail Of Pax6(s) Does Not Chsupporting

confidence: 93%

The β Subunit of Voltage-gated Ca2+ Channels Interacts with and Regulates the Activity of a Novel Isoform of Pax6

Zhang¹,

Yamada²,

Fan

et al. 2010

Journal of Biological Chemistry

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“…Expected sizes for PAX6 proteins are 46 kDa (canonical PAX6) and 48 kDa (PAX6(5a) and 3ϫFLAG-PAX6). Retinal tissues express both forms of PAX6 and are a size control for both isoforms (45). B, reverse transcription-PCR analysis for the expression of PAX6 and PAX6(5a) transcripts in MIAPACA-2 (lanes 1 and 2) and PANC-1 (lanes 3 and 4).…”

Section: Electrophoretic Mobility Shift Assay (Emsa)-whole Cell Extramentioning

confidence: 99%

PAX6 Is Expressed in Pancreatic Cancer and Actively Participates in Cancer Progression through Activation of the MET Tyrosine Kinase Receptor Gene

Mascarenhas

Young

Littlejohn

et al. 2009

Journal of Biological Chemistry

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Tumors of the exocrine pancreas have a poor prognosis. Several proteins are overexpressed in this cancer type, including the MET tyrosine kinase receptor and the transcription factor PAX6. In this report, we find that PAX6(5a), an alternately spliced variant form of PAX6, is expressed in pancreatic carcinoma cell lines at higher levels than the canonical PAX6 protein. Both protein forms of PAX6 bind directly to an enhancer element in the MET promoter and activate the expression of the MET gene. In addition, inhibition of PAX6 transcripts leads to a decline in cell growth and survival, differentiation, and a concurrent reduction of MET protein expression. These data support a model for a neoplastic pathway, where expression of a transcription factor from development activates the MET receptor, a protein that has been directly linked to protumorigenic processes of resisting apoptosis, tumor growth, invasion, and metastasis.Pancreatic cancer is an aggressive and deadly disease, with an average median survival of less than a year (1). Several genetic pathways have been identified as being active in the progression of this tumor, including signaling through MET (MET tyrosine kinase receptor protein). The MET gene encodes a tyrosine kinase receptor for the ligand hepatocyte growth factor/scatter factor. The MET gene produces a partially glycosylated 170-kDa precursor protein. This precursor is glycosylated further and cleaved into a 50-kDa ␣ chain and a 140-kDa ␤ chain to create a mature receptor (2). The MET receptor is essential for normal development and plays a role in cell migration, growth, survival, differentiation, angiogenesis, and tube formation/ branching morphogenesis (reviewed in Ref.3). MET has also been implicated in cancer progression and is directly involved in metastasis, resistance to apoptosis, and tumor growth.MET is expressed in the developing pancreatic bud of the embryo and marks candidate stem/progenitor cells in the embryonic and adult pancreas (4 -6). MET expression is expressed at very low levels in normal adult differentiated pancreatic cells (7). MET is overexpressed in pancreatic cancer cells and has been linked to the aggressiveness of this tumor in terms of growth, invasion, and metastasis (7-10).Although mutations in the MET locus have been identified, overexpression of MET occurs mainly due to aberrant transcriptional regulation (3). The MET gene is regulated by several transcription factors that can either activate or repress expression. Activators include HIF1 (hypoxia-induced factor 1) in response to oxygen deficiency (11), ETS1 (12), Sp1 (13), AP1 (14), Smads downstream of transforming growth factor-␤ signaling (13), and the p53 protein (15) The transcription factor PAX3 can also activate MET expression during the embryonic development of muscle cells (23). PAX3 belongs to the PAX gene family, and most of what is known about these related proteins is their role during development. Only recently has the expression of PAX proteins in adult stem cells and in disease been discovered...

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“…27 Although PAX6 was extensively studied during eye organogenesis in various species, little is known about PAX6 expression and function in adult eye tissues. PAX6 expression in the GCL and INL of the inner retina was observed in humans, 23 chicken, 28 and mouse 29 and Zhang et al 30 detected PAX6 expression in the adult lens epithelium. Bcl-2 indicates B-cell leukemia/lymphoma-2; Bcl-X L , B-cell leukemia/ lymphoma extra long; GFAP, glial fibrillary acidic protein; IL-1b, interleukin-1b; TIMP-1, tissue inhibitor of metalloproteinase-1; XIAP, X-linked inhibitor of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…De Melo et al 22 showed that several homeobox genes including Pax6 are expressed in the young adult mouse retina and we recently reported continuous expression of PAX6 in the young, adult, and old normal human retina. 23 To investigate the role of PAX6 expression in the adult eye and to assess whether PAX6 is involved in degenerative processes of the retina, we studied PAX6 expression in wild type and in calcitonin receptor-like receptor transgenic (CLR SMaA ) mice with acute angle-closure glaucoma (ACG). 24 …”

Section: Pax6 Expression and Retinal Cell Death In A Transgenicmentioning

confidence: 99%

PAX6 Expression and Retinal Cell Death in a Transgenic Mouse Model for Acute Angle-Closure Glaucoma

Stanescu-Segall¹,

Birke²,

Wenzel

et al. 2015

Journal of Glaucoma

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PURPOSE: PAX6 is a highly conserved protein essential for the control of eye development both in invertebrates and vertebrates. PAX6 expression persists in the adult inner retina, but little is known about its functions after completion of retinal differentiation. Therefore, we investigated PAX6 expression in wild-type and calcitonin receptor-like receptor transgenic (CLR) mice with angle-closure glaucoma. METHODS: Intraocular pressure was measured by indentation tonometry in anesthetized mice. Eyes of mice of both genotypes were enucleated at various ages and retinas were processed for morphological analysis and PAX6 immunostaining. The content of PAX6 in retinal extracts was estimated by Western blot analysis. Retinal expression of glaucoma-related genes was analyzed by reverse transcription-polymerase chain reaction. RESULTS: Control mice showed normal retinal morphology between p22 and p428 with steady PAX6 expression in the ganglion cell layer (GCL) and the inner nuclear layer (INL). CLR mice examined between p22 and p82 exhibited increased intraocular pressure and a progressive decrease in cell number including PAX6-expressing cells in the GCL. Originally published at: Stanescu-Segall, Dinu; Birke, Kerstin; Wenzel, Andreas; Grimm, Christian; Orgul, Sorguel; Fischer, Jan A; Born, Walter; Hafezi, Farhad (2015). PAX6 expression and retinal cell death in a transgenic mouse model for acute angle-closure glaucoma. Journal of Glaucoma, 24(6):426-432.

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Continuous expression of the homeobox gene Pax6 in the ageing human retina

Cited by 33 publications

References 17 publications

The β Subunit of Voltage-gated Ca2+ Channels Interacts with and Regulates the Activity of a Novel Isoform of Pax6

The β Subunit of Voltage-gated Ca2+ Channels Interacts with and Regulates the Activity of a Novel Isoform of Pax6

PAX6 Is Expressed in Pancreatic Cancer and Actively Participates in Cancer Progression through Activation of the MET Tyrosine Kinase Receptor Gene

PAX6 Expression and Retinal Cell Death in a Transgenic Mouse Model for Acute Angle-Closure Glaucoma

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