UniProt functional annotation for P19544



	UniProt functional annotation for P19544

UniProt code: P19544.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Transcription factor that plays an important role in cellular development and cell survival (PubMed:7862533). Recognizes and binds to the DNA sequence 5'-GCG(T/G)GGGCG-3' (PubMed:7862533, PubMed:17716689, PubMed:25258363). Regulates the expression of numerous target genes, including EPO. Plays an essential role for development of the urogenital system. It has a tumor suppressor as well as an oncogenic role in tumor formation. Function may be isoform-specific: isoforms lacking the KTS motif may act as transcription factors (PubMed:15520190). Isoforms containing the KTS motif may bind mRNA and play a role in mRNA metabolism or splicing (PubMed:16934801). Isoform 1 has lower affinity for DNA, and can bind RNA (PubMed:19123921). {ECO:0000269|PubMed:15520190, ECO:0000269|PubMed:16934801, ECO:0000269|PubMed:17716689, ECO:0000269|PubMed:19123921, ECO:0000269|PubMed:19416806, ECO:0000269|PubMed:25258363, ECO:0000269|PubMed:7862533}.

Subunit: Homodimer. Interacts with WTIP. Interacts with actively translating polysomes. Detected in nuclear ribonucleoprotein (mRNP) particles. Interacts with HNRNPU via the zinc-finger region. Interacts with U2AF2. Interacts with CITED2 (By similarity). Interacts with ZNF224 via the zinc-finger region. Interacts with WTAP and SRY. Interacts with AMER1. Interacts with RBM4. {ECO:0000250, ECO:0000269|PubMed:11001926, ECO:0000269|PubMed:12239212, ECO:0000269|PubMed:12970737, ECO:0000269|PubMed:15518539, ECO:0000269|PubMed:16934801, ECO:0000269|PubMed:17716689, ECO:0000269|PubMed:19416806}.

Subcellular location: Nucleus {ECO:0000269|PubMed:15520190}. Nucleus, nucleolus. Cytoplasm {ECO:0000250}. Note=Isoforms lacking the KTS motif have a diffuse nuclear location (PubMed:15520190). Shuttles between nucleus and cytoplasm. {ECO:0000250, ECO:0000269|PubMed:15520190}.

Subcellular location: [Isoform 1]: Nucleus speckle {ECO:0000269|PubMed:15520190}.

Subcellular location: [Isoform 4]: Nucleus, nucleoplasm {ECO:0000269|PubMed:15520190}.

Tissue specificity: Expressed in the kidney and a subset of hematopoietic cells.

Domain: Binds to DNA motifs with the sequence 5'-GCG(T/G)GGGCG-3' via its C2H2-type zinc fingers. Starting from the N-terminus, the second zinc finger binds to the 3'-GCG motif, the middle zinc finger interacts with the central TGG motif, and the C-terminal zinc finger binds to the 5'-GCG motif. Binds double-stranded target DNA, irrespective of the cytosine methylation status. Has reduced affinity for target DNA where the cytosines have been oxidized to 5-hydroxymethylcytosine, 5- formylcytosine or 5-carboxylcytosine. {ECO:0000269|PubMed:25258363}.

Domain: The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors. {ECO:0000269|PubMed:31375868}.

Rna editing: Modified_positions=281 {ECO:0000269|PubMed:7926762}; Note=Partially edited.;

Disease: Frasier syndrome (FS) [MIM:136680]: Characterized by a slowly progressing nephropathy leading to renal failure in adolescence or early adulthood, male pseudohermaphroditism, and no Wilms tumor. As for histological findings of the kidneys, focal glomerular sclerosis is often observed. There is phenotypic overlap with Denys-Drash syndrome. Inheritance is autosomal dominant. {ECO:0000269|PubMed:10571943}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Wilms tumor 1 (WT1) [MIM:194070]: Embryonal malignancy of the kidney that affects approximately 1 in 10'000 infants and young children. It occurs both in sporadic and hereditary forms. {ECO:0000269|PubMed:1317572, ECO:0000269|PubMed:15150775, ECO:0000269|PubMed:9108089, ECO:0000269|PubMed:9529364}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Denys-Drash syndrome (DDS) [MIM:194080]: Typical nephropathy characterized by diffuse mesangial sclerosis, genital abnormalities, and/or Wilms tumor. There is phenotypic overlap with WAGR syndrome and Frasier syndrome. Inheritance is autosomal dominant, but most cases are sporadic. {ECO:0000269|PubMed:10738002, ECO:0000269|PubMed:10799199, ECO:0000269|PubMed:11182928, ECO:0000269|PubMed:11519891, ECO:0000269|PubMed:1302008, ECO:0000269|PubMed:1338906, ECO:0000269|PubMed:15349765, ECO:0000269|PubMed:1655284, ECO:0000269|PubMed:8111391, ECO:0000269|PubMed:8112732, ECO:0000269|PubMed:8295405, ECO:0000269|PubMed:8388765, ECO:0000269|PubMed:8411073, ECO:0000269|PubMed:8741319, ECO:0000269|PubMed:8956030, ECO:0000269|PubMed:9475094, ECO:0000269|PubMed:9529364}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Nephrotic syndrome 4 (NPHS4) [MIM:256370]: A form of nephrotic syndrome, a renal disease clinically characterized by severe proteinuria, resulting in complications such as hypoalbuminemia, hyperlipidemia and edema. Kidney biopsies show non-specific histologic changes such as focal segmental glomerulosclerosis and diffuse mesangial proliferation. Some affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure. Most patients with NPHS4 show diffuse mesangial sclerosis on renal biopsy, which is a pathologic entity characterized by mesangial matrix expansion with no mesangial hypercellularity, hypertrophy of the podocytes, vacuolized podocytes, thickened basement membranes, and diminished patency of the capillary lumen. {ECO:0000269|PubMed:11182928, ECO:0000269|PubMed:15253707, ECO:0000269|PubMed:20798252, ECO:0000269|PubMed:9529364, ECO:0000269|PubMed:9607189}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Meacham syndrome (MEACHS) [MIM:608978]: Rare sporadically occurring multiple malformation syndrome characterized by male pseudohermaphroditism with abnormal internal female genitalia comprising a uterus and double or septate vagina, complex congenital heart defect and diaphragmatic abnormalities. {ECO:0000269|PubMed:17853480}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Note=A chromosomal aberration involving WT1 may be a cause of desmoplastic small round cell tumor (DSRCT). Translocation t(11;22)(p13;q12) with EWSR1.

Disease: Mesothelioma, malignant (MESOM) [MIM:156240]: An aggressive neoplasm of the serosal lining of the chest. It appears as broad sheets of cells, with some regions containing spindle-shaped, sarcoma-like cells and other regions showing adenomatous patterns. Pleural mesotheliomas have been linked to exposure to asbestos. {ECO:0000269|PubMed:8401592}. Note=The disease may be caused by variants affecting the gene represented in this entry.

Miscellaneous: Presence of the KTS motif hinders interactions between DNA and zinc-finger 4.

Miscellaneous: [Isoform 1]: Detected in nucleus speckle, may bind mRNA.

Miscellaneous: [Isoform 7]: Produced by alternative initiation of isoform 1. Extended N-terminus. {ECO:0000305}.

Miscellaneous: [Isoform 8]: Produced by alternative initiation of isoform 1. Extended N-terminus. {ECO:0000305}.

Similarity: Belongs to the EGR C2H2-type zinc-finger protein family. {ECO:0000305}.

Sequence caution: Sequence=AAB33443.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the N-terminal part.; Evidence={ECO:0000305}; Sequence=CAA35956.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; Sequence=CAA35956.1; Type=Miscellaneous discrepancy; Note=Unusual initiator. The initiator methionine is coded by a non-canonical CTG leucine codon.; Evidence={ECO:0000305}; Sequence=CAC39220.3; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; Sequence=CAI95758.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; Sequence=CAI95759.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Transcription factor that plays an important role in cellular development and cell survival (PubMed:7862533). Recognizes and binds to the DNA sequence 5'-GCG(T/G)GGGCG-3' (PubMed:7862533, PubMed:17716689, PubMed:25258363). Regulates the expression of numerous target genes, including EPO. Plays an essential role for development of the urogenital system. It has a tumor suppressor as well as an oncogenic role in tumor formation. Function may be isoform-specific: isoforms lacking the KTS motif may act as transcription factors (PubMed:15520190). Isoforms containing the KTS motif may bind mRNA and play a role in mRNA metabolism or splicing (PubMed:16934801). Isoform 1 has lower affinity for DNA, and can bind RNA (PubMed:19123921). {ECO:0000269\|PubMed:15520190, ECO:0000269\|PubMed:16934801, ECO:0000269\|PubMed:17716689, ECO:0000269\|PubMed:19123921, ECO:0000269\|PubMed:19416806, ECO:0000269\|PubMed:25258363, ECO:0000269\|PubMed:7862533}.


Subunit:		Homodimer. Interacts with WTIP. Interacts with actively translating polysomes. Detected in nuclear ribonucleoprotein (mRNP) particles. Interacts with HNRNPU via the zinc-finger region. Interacts with U2AF2. Interacts with CITED2 (By similarity). Interacts with ZNF224 via the zinc-finger region. Interacts with WTAP and SRY. Interacts with AMER1. Interacts with RBM4. {ECO:0000250, ECO:0000269\|PubMed:11001926, ECO:0000269\|PubMed:12239212, ECO:0000269\|PubMed:12970737, ECO:0000269\|PubMed:15518539, ECO:0000269\|PubMed:16934801, ECO:0000269\|PubMed:17716689, ECO:0000269\|PubMed:19416806}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:15520190}. Nucleus, nucleolus. Cytoplasm {ECO:0000250}. Note=Isoforms lacking the KTS motif have a diffuse nuclear location (PubMed:15520190). Shuttles between nucleus and cytoplasm. {ECO:0000250, ECO:0000269\|PubMed:15520190}.
Subcellular location:		[Isoform 1]: Nucleus speckle {ECO:0000269\|PubMed:15520190}.
Subcellular location:		[Isoform 4]: Nucleus, nucleoplasm {ECO:0000269\|PubMed:15520190}.
Tissue specificity:		Expressed in the kidney and a subset of hematopoietic cells.
Domain:		Binds to DNA motifs with the sequence 5'-GCG(T/G)GGGCG-3' via its C2H2-type zinc fingers. Starting from the N-terminus, the second zinc finger binds to the 3'-GCG motif, the middle zinc finger interacts with the central TGG motif, and the C-terminal zinc finger binds to the 5'-GCG motif. Binds double-stranded target DNA, irrespective of the cytosine methylation status. Has reduced affinity for target DNA where the cytosines have been oxidized to 5-hydroxymethylcytosine, 5- formylcytosine or 5-carboxylcytosine. {ECO:0000269\|PubMed:25258363}.
Domain:		The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors. {ECO:0000269\|PubMed:31375868}.
Rna editing:		Modified_positions=281 {ECO:0000269\|PubMed:7926762}; Note=Partially edited.;
Disease:		Frasier syndrome (FS) [MIM:136680]: Characterized by a slowly progressing nephropathy leading to renal failure in adolescence or early adulthood, male pseudohermaphroditism, and no Wilms tumor. As for histological findings of the kidneys, focal glomerular sclerosis is often observed. There is phenotypic overlap with Denys-Drash syndrome. Inheritance is autosomal dominant. {ECO:0000269\|PubMed:10571943}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Wilms tumor 1 (WT1) [MIM:194070]: Embryonal malignancy of the kidney that affects approximately 1 in 10'000 infants and young children. It occurs both in sporadic and hereditary forms. {ECO:0000269\|PubMed:1317572, ECO:0000269\|PubMed:15150775, ECO:0000269\|PubMed:9108089, ECO:0000269\|PubMed:9529364}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Denys-Drash syndrome (DDS) [MIM:194080]: Typical nephropathy characterized by diffuse mesangial sclerosis, genital abnormalities, and/or Wilms tumor. There is phenotypic overlap with WAGR syndrome and Frasier syndrome. Inheritance is autosomal dominant, but most cases are sporadic. {ECO:0000269\|PubMed:10738002, ECO:0000269\|PubMed:10799199, ECO:0000269\|PubMed:11182928, ECO:0000269\|PubMed:11519891, ECO:0000269\|PubMed:1302008, ECO:0000269\|PubMed:1338906, ECO:0000269\|PubMed:15349765, ECO:0000269\|PubMed:1655284, ECO:0000269\|PubMed:8111391, ECO:0000269\|PubMed:8112732, ECO:0000269\|PubMed:8295405, ECO:0000269\|PubMed:8388765, ECO:0000269\|PubMed:8411073, ECO:0000269\|PubMed:8741319, ECO:0000269\|PubMed:8956030, ECO:0000269\|PubMed:9475094, ECO:0000269\|PubMed:9529364}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Nephrotic syndrome 4 (NPHS4) [MIM:256370]: A form of nephrotic syndrome, a renal disease clinically characterized by severe proteinuria, resulting in complications such as hypoalbuminemia, hyperlipidemia and edema. Kidney biopsies show non-specific histologic changes such as focal segmental glomerulosclerosis and diffuse mesangial proliferation. Some affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure. Most patients with NPHS4 show diffuse mesangial sclerosis on renal biopsy, which is a pathologic entity characterized by mesangial matrix expansion with no mesangial hypercellularity, hypertrophy of the podocytes, vacuolized podocytes, thickened basement membranes, and diminished patency of the capillary lumen. {ECO:0000269\|PubMed:11182928, ECO:0000269\|PubMed:15253707, ECO:0000269\|PubMed:20798252, ECO:0000269\|PubMed:9529364, ECO:0000269\|PubMed:9607189}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Meacham syndrome (MEACHS) [MIM:608978]: Rare sporadically occurring multiple malformation syndrome characterized by male pseudohermaphroditism with abnormal internal female genitalia comprising a uterus and double or septate vagina, complex congenital heart defect and diaphragmatic abnormalities. {ECO:0000269\|PubMed:17853480}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Note=A chromosomal aberration involving WT1 may be a cause of desmoplastic small round cell tumor (DSRCT). Translocation t(11;22)(p13;q12) with EWSR1.
Disease:		Mesothelioma, malignant (MESOM) [MIM:156240]: An aggressive neoplasm of the serosal lining of the chest. It appears as broad sheets of cells, with some regions containing spindle-shaped, sarcoma-like cells and other regions showing adenomatous patterns. Pleural mesotheliomas have been linked to exposure to asbestos. {ECO:0000269\|PubMed:8401592}. Note=The disease may be caused by variants affecting the gene represented in this entry.
Miscellaneous:		Presence of the KTS motif hinders interactions between DNA and zinc-finger 4.
Miscellaneous:		[Isoform 1]: Detected in nucleus speckle, may bind mRNA.
Miscellaneous:		[Isoform 7]: Produced by alternative initiation of isoform 1. Extended N-terminus. {ECO:0000305}.
Miscellaneous:		[Isoform 8]: Produced by alternative initiation of isoform 1. Extended N-terminus. {ECO:0000305}.
Similarity:		Belongs to the EGR C2H2-type zinc-finger protein family. {ECO:0000305}.
Sequence caution:		Sequence=AAB33443.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the N-terminal part.; Evidence={ECO:0000305}; Sequence=CAA35956.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; Sequence=CAA35956.1; Type=Miscellaneous discrepancy; Note=Unusual initiator. The initiator methionine is coded by a non-canonical CTG leucine codon.; Evidence={ECO:0000305}; Sequence=CAC39220.3; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; Sequence=CAI95758.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; Sequence=CAI95759.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};