Related Experiment Video
Updated: Aug 8, 2026
Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
Published on: June 27, 2020
N-terminally truncated WT1 protein with oncogenic properties overexpressed in leukemia
Anwar Hossain1, Molly Nixon, Macus T Kuo
1Department of Biochemistry and Molecular Biology, The University of Texas M. D. Anderson Cancer Center, Houston, 77054, USA. ahossain@mdanderson.org
Abstract:
WT1 was originally identified as an inactivated gene in Wilms tumor, a childhood kidney cancer. Alternative splicing of the WT1 transcript generates four major protein isoforms, each having different functional properties. Here we characterized a short transcript originating from a second promoter located within intron 1 of WT1. This 2.3-kb sWT1 transcript encodes a protein of approximately 35-37 kDa that retains intact DNA-binding and transactivation domains but lacks the 147 amino acids at the N terminus required for transcriptional repression. We found sWT1 to be a more potent transcriptional activator than WT1 for cyclin E and insulin-like growth factor 1 receptor promoters, which are normally repressed by WT1. The expression patterns of the sWT1 and WT1 transcripts differed slightly in various organs; we found sWT1 protein in tissue samples from adult testis and fetal kidney, with low-level expression in adult kidney as well. The sWT1 transcript, but not the full-length transcript, was over-expressed in the leukemia samples tested. sWT1-specific small interfering RNA retarded the proliferation of leukemia cell line K562 in vitro. Finally, sWT1 cooperated with Ras in transforming primary fibroblasts in vitro. Further studies are needed to clarify the oncogenic behavior of this isoform and to determine the mechanism underlying its up-regulation in leukemia and other forms of cancer.
Insights
A newly identified WT1 splice variant, sWT1, acts as a potent activator of gene expression and is overexpressed in leukemia, suggesting a role in cancer development.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- The Wilms tumor (WT1) gene is crucial in kidney development and cancer.
- WT1 has multiple isoforms generated by alternative splicing, influencing its function.
- WT1 normally functions in transcriptional repression.
Purpose of the Study:
- To characterize a novel, short WT1 transcript (sWT1) originating from an intronic promoter.
- To investigate the functional properties and expression patterns of sWT1.
- To explore the role of sWT1 in leukemia and oncogenesis.
Main Methods:
- Transcriptional analysis of sWT1 and WT1.
- Protein characterization of sWT1.
- Expression profiling in various tissues and leukemia samples.
- Functional assays including siRNA knockdown and Ras cooperation in cell transformation.
Main Results:
- A 2.3-kb sWT1 transcript encodes a protein retaining DNA-binding and transactivation domains but lacking the repression domain.
- sWT1 is a stronger activator than WT1 for specific promoters (cyclin E, IGF1R).
- sWT1 is expressed in adult testis, fetal and adult kidney, and is overexpressed in leukemia.
- sWT1 knockdown inhibits leukemia cell proliferation, and sWT1 cooperates with Ras in fibroblast transformation.
Conclusions:
- sWT1 represents a distinct WT1 isoform with potent transcriptional activation properties.
- The overexpression of sWT1 in leukemia suggests its potential as an oncogenic factor.
- Further research is warranted to elucidate the oncogenic mechanisms of sWT1 and its role in various cancers.
Related Concept Videos
02:54Canonical Wnt Signaling Pathway
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:33Cancer-Critical Genes I: Proto-oncogenes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
02:23Abnormal Proliferation
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...