BASP1 Is a Transcriptional Cosuppressor for the Wilms' Tumor Suppressor Protein WT1

Abstract

The Wilms' tumor suppressor protein WT1 is a transcriptional regulator that plays a key role in the development of the kidneys. The transcriptional activation domain of WT1 is subject to regulation by a suppression region within the N terminus of WT1. Using a functional assay, we provide direct evidence that this requires a transcriptional cosuppressor, which we identify as brain acid soluble protein 1 (BASP1). WT1 and BASP1 associate within the nuclei of cells that naturally express both proteins. BASP1 can confer WT1 cosuppressor activity in transfection assays, and elimination of endogenous BASP1 expression augments transcriptional activation by WT1. BASP1 is present in the developing nephron structures of the embryonic kidney and, coincident with that of WT1, its expression is restricted to the highly specialized podocyte cells of the adult kidney. Taken together, our results show that BASP1 is a WT1-associated factor that can regulate WT1 transcriptional activity.Wilms' tumor, a pediatric malignancy of the kidneys, is the most common solid childhood tumor (reviewed in references 4, 7, 20, 30, and 33). The isolation of genes associated with Wilms' tumor led to the identification of a zinc finger protein, WT1. Subsequently, WT1 was shown to be a transcriptional regulator with putative target genes including those for growth factors and regulators of cell division (5,6,18,21). Approximately 15% of sporadic Wilms' tumors have been found to contain mutations in WT1, while others show aberrant WT1 expression (33).WT1 knockout mice (homozygous null) do not survive gestation, displaying absence or incorrect development of the kidney, gonads, spleen, heart, diaphragm, and retinal ganglia (12,14,35). These findings confirm a major role for WT1 in the formation of the genitourinary system and also a wider role in the development of other tissues.Alternative splicing, RNA editing, and an alternative translation start codon combine to produce a plethora of WT1 isoforms (reviewed in reference 33). One alternative splice inserts three amino acids (KTS) between zinc fingers three and four, resulting in a form of WT1 that associates with RNA processing factors and localizes to regions of RNA processing in the nucleus (17). Thus, the ϩKTS and ϪKTS isoforms of WT1 have been proposed to function in RNA processing and transcription, respectively. These isoforms have both overlapping and distinct roles during development (9, 10). Interestingly, the ϩKTS isoform of WT1 plays the dominant role in the development of the gonad, while the ϪKTS isoform has a more extensive function in kidney formation.The other alternative splice inserts 17 amino acids N terminal to the WT1 zinc fingers and has been shown to have effects on both cell division and cell survival (15,31,32). Specific elimination of this isoform of WT1 in mice does not result in any obvious defects in genitourinary development, suggesting that it may be required specifically for a tumor suppressor role or that it performs a subtle function (28).Several studies have shown ...

BASP1 Promotes Apoptosis in Diabetic Nephropathy

“…Low levels of BASP1 expression are present in the cytoplasm of tubular cells in vivo and in cell lines. 15 BASP1 expression is increased in human DN tubulointerstitium and in tubules from experimental DN. BASP1 is also expressed by cultured renal tubular cells, where it is regulated by stimuli that promote cell death and has a role in apoptotic cell death.…”

“…12 It was initially described as a brain-specific protein, 10,11 but later studies revealed that BASP1 is also expressed by human endothelium, 13 developing mammary gland, kidney, testis, and lymphoid tissues. [12][13][14][15][16] BASP1 is involved in cytoskeletal and lipid raft dynamics, as well as in the nuclear regulation of transcription. However, a role in apoptosis has not been previously reported.…”

hnRNP-U directly interacts with WT1 and modulates WT1 transcriptional activation

“…A luciferase reporter gene under the control of the amphiregulin promoter, with and without WT1-binding sites, was transfected into NIH 3T3 cells in the presence or absence of hnRNP-U. As previously described, WT1 activated reporter gene expression (Figure 4f) (Carpenter et al, 2004). However, cotransfection with hnRNP-U significantly reduced (50%) (Po0.0000175 and 0.000145) WT1 activation, but had little effect when transfected alone (Figure 4f) and did not affect expression of WT1 itself -WT1 protein is still highly expressed in the presence of transfected hnRNP-U (Figure 4e).…”

Integrated Network Analysis of Genetic and Epigenetic Factors in Glioblastoma Multiform

“…mir-21 was found to be over expressed in multiple cancers and down regulated tumor suppressor genes: TPM1, PTEN, PDCD4 BASP1 and RTN4 in invasion and metastasis of cancer (Yang, et al, 2009). BASP1 is a transcriptional cosuppressor for the Wilms' tumor suppressor protein WT1, thus it can regulate WT1 transcriptional activity (Carpenter, et al, 2004). Nogo-A , one protein isoforms encoded by RTN4, had turned out to be a neuronal protein involved in diverse processes that go from axonal fasciculation to apoptosis (Mingorance, et al, 2004).…”