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PMID:20624457

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Citation

Wang, H, Yang, Y, Sharma, N, Tarasova, NI, Timofeeva, OA, Winkler-Pickett, RT, Tanigawa, S and Perantoni, AO (2010) STAT1 activation regulates proliferation and differentiation of renal progenitors. Cell. Signal. 22:1717-26

Abstract

We have shown previously that activation of STAT1 contributes to the pathogenesis of Wilms tumor. This neoplasm caricatures metanephric development and is believed to originate from embryonic renal mesenchymal progenitors that lose their ability to undergo mesenchymal-epithelial transition (MET). Therefore, we hypothesized that STAT1 is also activated and functional during metanephric development. Here we have demonstrated that both STAT1 and STAT3 are activated during normal development of the embryonic kidney. Furthermore, activation of STAT1 stimulated the proliferation of metanephric mesenchymal cells, but it prevented MET and tubulogenesis induced by leukemia inhibitory factor, which preferentially activates STAT3. Consistent with its negative regulation of metanephric mesenchymal differentiation, inhibition of STAT1 activation with protein kinase CK2 inhibitor TBB or RNAi-mediated knockdown of STAT1 promoted differentiation of metanephric progenitors and abolished the effect of cytokine-induced STAT1 activation in these cells. Additionally, a cell-permeable peptide that inhibits STAT1-mediated transactivation by targeting the STAT1 N-domain also blocked cytokine-induced STAT1-dependent proliferation in metanephric progenitors and promoted LIF-induced MET and tubulogenesis. Finally, the STAT1 peptide inhibitor caused the down regulation of survival/anti-apoptotic factors, Mcl-1 and Hsp-27, and induced apoptosis in renal tumor cells with constitutively active STAT1, indicating that STAT1 is required for these cells to survive. These findings show that both metanephric progenitors and renal tumor cells utilize a STAT1-dependent mechanism for growth or survival.

Links

PubMed PMC2923257 Online version:10.1016/j.cellsig.2010.06.012

Keywords

Apoptosis; Casein Kinase II/antagonists & inhibitors; Casein Kinase II/metabolism; Cell Differentiation; Cell Proliferation; HSP27 Heat-Shock Proteins/metabolism; Humans; Interferon-gamma/pharmacology; Kidney/cytology; Kidney/embryology; Leukemia Inhibitory Factor/metabolism; Mesenchymal Stem Cells/cytology; Proto-Oncogene Proteins c-bcl-2/metabolism; RNA Interference; STAT1 Transcription Factor/antagonists & inhibitors; STAT1 Transcription Factor/metabolism; STAT3 Transcription Factor/antagonists & inhibitors; STAT3 Transcription Factor/metabolism; Transcriptional Activation

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:LIF

GO:0042511: positive regulation of tyrosine phosphorylation of Stat1 protein

ECO:0000314:

P

B-C. LIF activates STAT1 in MM.

complete

RAT:LIF

GO:0042517: positive regulation of tyrosine phosphorylation of Stat3 protein

ECO:0000314:

P

LIF activates STAT3 in MM

complete

RAT:LIF

Contributes to

GO:0072162: metanephric mesenchymal cell differentiation

ECO:0000314:

P

"...indicating that STAT1 is also activated in early renal development".

(Since LIF is upstream of STAT1, it contributes to metanephric mesenchymal cell differentiation by activating STAT1).

complete

RAT:LIF

GO:0051091: positive regulation of transcription factor activity

ECO:0000314:

P

As shown in Fig.3A, LIF ...induced the expression of LIM-1.

"The Lim-1 gene encodes a LIM-homeodomain transcription factor that is highly conserved among vertebrates". definition from PMID:12454922[1].


complete

RAT:LIF

GO:0046587: positive regulation of calcium-dependent cell-cell adhesion

ECO:0000314:

P

..we also evaluated expression of lim-1 and E-cadherin by immunoblotting. Expression of both markers was induced with LIF treatment.

E-cadherin - definition from UniProt Cadherins are calcium-dependent cell adhesion proteins





complete

RAT:IFNG

GO:0042511: positive regulation of tyrosine phosphorylation of Stat1 protein

ECO:0000314:

P

INF-G activates only STAT1 in metanephric mesenchymes

complete

RAT:IFNG

GO:0002053: positive regulation of mesenchymal cell proliferation

ECO:0000314:

P

INF-G-induced cell proliferation became evident after one day of treatment....(Fig2C).

complete

RAT:IFNG

GO:0043433: negative regulation of transcription factor activity

ECO:0000314:

P

The presence of INF-G with LIF or CM supressed Lim-1 production. Fig 3e.

"The Lim-1 gene encodes a LIM-homeodomain transcription factor that is highly conserved among vertebrates" -definition of Lim-1 from PMID:12454922[1]

complete

RAT:IFNG

GO:0046588: negative regulation of calcium-dependent cell-cell adhesion

ECO:0000314:

P

The suppression of LIF-induced differentiation markers lim-1 and E-cadherin by INF-G was also demo. by semi-quantitative RT-PCR analysis.

From UniProt definition of E-cadherin: "Cadherins are calcium-dependent cell adhesion proteins"

complete

RAT:IFNG

GO:0003340: negative regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis

ECO:0000314:

P

...these results indicate that INF-G stimulates proliferation of mesenchymal cells and abrogates LIF-induced MET and tubulogenesis.

complete

RAT:IFNG

GO:0072308: negative regulation of metanephric nephron tubule epithelial cell differentiation

ECO:0000314:

P

...these results indicate that INF-G stimulates proliferation of mesenchymal cells and abrogates LIF-induced MET and tubulogenesis

complete

RAT:IFNG

GO:0000122: negative regulation of transcription from RNA polymerase II promoter

ECO:0000314:

P

complete

RAT:IFNG

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:IFNG

involved_in

GO:0008284: positive regulation of cell population proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:IFNG

involved_in

GO:0033141: positive regulation of peptidyl-serine phosphorylation of STAT protein

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:IFNG

involved_in

GO:0042531: positive regulation of tyrosine phosphorylation of STAT protein

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:IFNG

involved_in

GO:0030857: negative regulation of epithelial cell differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:Q9QXK0

GO:0045941: positive regulation of transcription

ECO:0000315:

P

knockdown of STAT1 significantly reduced the expression of vimentin fig 4f.

complete

RAT:Q9QXK0

GO:0046588: negative regulation of calcium-dependent cell-cell adhesion

ECO:0000315:

P

knockdown of STAT1 ..... It also enhanced expression of the epithelial cell marker E-cadherin.

complete

RAT:Q9QXK0

GO:0090184: positive regulation of kidney development

ECO:0000314:

P

Although both STAT1 and STAT3 are present in adult rat kidney, little phosphorylated STAT1 and STAT3 can be detected indicating that they are not activated once development ceases (Fig 1 A)

complete

RAT:Q9QXK0

GO:0008284: positive regulation of cell proliferation

ECO:0000269:

P

Fig 5. STAT1 inhibitor H2-2 treatment accelerates ....and inhibits cell proliferation

complete

RAT:Q9QXK0

GO:0045596: negative regulation of cell differentiation

ECO:0000269:

P

STAT-1 inhibitor H2-2 treatment accelerates MMs differentiation

Ideal GO term would be negative regulation of mesenchymal cell differentiation, but does not exist

complete

RAT:Q9QXK0

GO:0043065: positive regulation of apoptosis

ECO:0000314:

P

Fig 5, d.e Inhibition of STAT1 induced apoptosis of cancer cells

complete

RAT:Q9QXK0

GO:0030307: positive regulation of cell growth

ECO:0000314:

P

Fig 5 c. Inhibition of STAT1 attenuates growth

complete

RAT:Q9QXK0

involved_in

GO:0072136: metanephric mesenchymal cell proliferation involved in metanephros development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:Q9QXK0

involved_in

GO:0002053: positive regulation of mesenchymal cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:Q9QXK0

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:Q9QXK0

involved_in

GO:0072162: metanephric mesenchymal cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:Q9QXK0

involved_in

GO:0003340: negative regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:Q9QXK0

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:Q9QXK0

involved_in

GO:0072308: negative regulation of metanephric nephron tubule epithelial cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:STAT3

GO:0090184: positive regulation of kidney development

ECO:0000314:

P

Although both STAT1 and STAT3 are present in adult rat kidney, little phosphorylated STAT1 and STAT3 can be detected indicating that they are not activated once development ceases (Fig 1 A)

complete

HUMAN:LIF

involved_in

GO:0072307: regulation of metanephric nephron tubule epithelial cell differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LIF

involved_in

GO:0072108: positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LIF

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LIF

involved_in

GO:0042531: positive regulation of tyrosine phosphorylation of STAT protein

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LIF

involved_in

GO:0033141: positive regulation of peptidyl-serine phosphorylation of STAT protein

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

See Help:References for how to manage references in GONUTS.

  1. 1.0 1.1 Watanabe, M et al. (2002) Regulation of the Lim-1 gene is mediated through conserved FAST-1/FoxH1 sites in the first intron. Dev. Dyn. 225 448-56 PubMed GONUTS page