Biomedical subjects

F J Rauscher

Publications and source records attributed to F J Rauscher.

At least 55 records · Page 3Linked to original sources

PubMed1996

Cell cycle regulation of BRCA1 messenger RNA in human breast epithelial cells.

BRCA1 was originally isolated as a gene that conferred susceptibility to early-onset familial breast and ovarian cancers. The function and regulation of this gene is presently unknown. Northern blot analyses using probes that recognize different regions of the BRCA1 cDNA revealed the presence of at least two distinct mRNA species. In synchronized normal and immortalized human mammary epithelial cells, BRCA1 mRNA levels were high in exponentially growing populations, decreased upon growth factor withdrawal, and subsequently increased again in late G1 just prior to S-phase entry. BRCA1 mRNA levels were found to be dramatically reduced in senescent normal human mammary epithelial cells and in normal human mammary epithelial cells treated with transforming growth factor beta 1. When considered together, these data indicate that expression of BRCA1 mRNA is highly sensitive to changes in growth conditions in vitro. BRCA1 proteins with apparent molecular weights of M(r) 210,000, 185,000, 160,000, 135,000, and 85,000, respectively, were detected at varying levels in all breast epithelial cells examined. Further molecular characterization of the nature and function of the different BRCA1 mRNAs and proteins should increase our understanding of this gene in the etiology of human breast cancers.

Breast↗

PubMed1995

LLC-PK1 cell growth is repressed by WT1 inhibition of G-protein alpha i-2 protooncogene transcription.

The temporal expression of the early growth response gene (EGR-1) is one molecular mechanism for both maximal activation of the G alpha i-2 gene and accelerated growth in mitotically active predifferentiated LLC-PK1 renal cells. These events are dependent on an enhancer area in the 5'-flanking region of the G alpha i-2 gene that contains an EGR-1 motif (5'-CGCCCCCGC-3'). However, acquisition of the polarized phenotype in LLC-PK1 cells is accompanied by loss of EGR-1 expression and occupancy of the EGR-1 site by nuclear binding proteins other than EGR-1. We now demonstrate that one of these binding proteins is the Wilms' tumor suppressor (WT1). Furthermore, the temporal expression of WT1 in LLC-PK1 cells acquiring the polarized phenotype represses both G alpha i-2 gene activation and growth in these cells. These findings suggest the existence of differentiation-induced pathways in LLC-PK1 cells that alternatively abrogates EGR-1 and promotes WT1 gene expression, thereby modulating a target protooncogene G alpha i-2 that is participatory for growth and differentiation in renal cells. These studies emphasize the usefulness of the LLC-PK1 renal cell as a model to elucidate normal programs of genetic differentiation in which WT1 participates.

Animals↗

PubMed1995

The myeloid zinc finger gene, MZF-1, regulates the CD34 promoter in vitro.

MZF-1 is a C2H2 zinc finger gene encoding a putative transcriptional regulator of myeloid differentiation. The MZF-1 protein contains 13 C2H2 zinc fingers arranged in bipartite DNA binding domains containing zinc fingers through 4 and, in the carboxy-terminus, 5 through 13. We previously identified the DNA consensus binding site recognized by the two DNA binding domains. To assess the transcription regulatory function of MZF-1, the full-length MZF-1 coding region was fused to the DNA binding domain of the yeast transactivator GAL4. The expression vector was cotransfected with the chloramphenicol acetyl transferase (CAT) reporter gene regulated by the thymidine kinase promoter containing GAL4 DNA binding sites into NIH 3T3, 293, K562, and Jurkat cell lines. MZF-1 represses CAT reporter gene expression via GAL4 binding sites in the nonhematopoietic cell lines NIH 3T3 and 293. In contrast, MZF-1 activates CAT reporter gene expression in the hematopoietic cell lines K562 and Jurkat. The MZF-1 binding sites are present in the promoters of several genes expressed during myeloid differentiation, including the CD34 promoter. MZF-1 transcriptional regulation of this physiologically relevant promoter was assessed in both hematopoietic and nonhematopoietic cell lines. Recombinant MZF-1 protein specifically binds to the consensus binding sites in the CD34 promoter in mobility shift assays. MZF-1 expression vectors were cotransfected with the luciferase reporter plasmids regulated by the CD34 promoter into both nonhematopoietic and hematopoietic cell lines. As with the heterologous DNA binding domain, MZF-1 represses reporter gene expression in nonhematopoietic cell lines and activates expression in hematopoietic cell lines. Activation of CD34 expression in hematopoietic cell lines is dependent on the presence of intact MZF-1 binding sites. The cell type-specific regulation of the CD34 promoter by MZF-1 suggests the presence of tissue-specific regulators/adapters or differential MZF-1 modifications that determine MZF-1 transcriptional regulatory function.

3T3 Cells↗

PubMed1995

Regulation of the proto-oncogenes bcl-2 and c-myc by the Wilms' tumor suppressor gene WT1.

The Wilms' tumor gene WT1 functions as a tumor suppressor gene, repressing transcription of several growth factors and growth factor receptors. The bcl-2 and c-myc proto-oncogenes are essential for regulation of apoptosis and cell proliferation with roles in development and oncogenesis. We found that WT1 can repress transcription of both the bcl-2 and c-myc promoters. This suggests that WT1 regulates bcl-2 and c-myc during renal development, and the loss of functional WT1 results in deregulation of bcl-2 and c-myc, contributing to tumor formation.

Amino Acid Sequence↗

PubMed1995

Wild type PAX3 protein and the PAX3-FKHR fusion protein of alveolar rhabdomyosarcoma contain potent, structurally distinct transcriptional activation domains.

Alveolar rhabdomyosarcoma (ARMS) is characterized cytogenetically by a t(2;13)(q35;q14) chromosomal translocation involving two transcription factor genes: PAX3 and FKHR. ARMS cells express a PAX3-FKHR fusion protein containing the complete N-terminal, DNA-binding domain of PAX3 and the C-terminus of FKHR. Recently we demonstrated that PAX3-FKHR is a more potent transcriptional activator than PAX3 despite impaired binding to canonical PAX3 binding sites. Therefore, we propose that the gene fusion results in switching of PAX3 and FKHR transactivation domains with distinct structure, potency or function. To compare the PAX3 and putative PAX3-FKHR transactivation domains, we fused C-terminal test fragments to the heterologous GAL4 DNA-binding domain and tested activation of a reporter gene co-transfected into four cell types. GAL4-PAX3 and GAL4-PAX3-FKHR were found to be potent activators exhibiting different concentration-dependent transactivation profiles and distinct structural motifs. Deletion mapping demonstrated essential acidic and/or serine/threonine-rich domains in the extreme 3' ends of their respective coding regions and positive modifying elements in adjacent 5' sequences. These data demonstrate that PAX3 and PAX3-FKHR contain structurally distinct transcriptional activation domains and suggest that a consequent difference in function is important for oncogenesis.

3T3 Cells↗

PubMed1995

The PAX3-FKHR fusion protein created by the t(2;13) translocation in alveolar rhabdomyosarcomas is a more potent transcriptional activator than PAX3.

Alveolar rhabdomyosarcomas are pediatric solid tumors with a hallmark cytogenetic abnormality: translocation of chromosomes 2 and 13 [t(2;13) (q35;q14)]. The genes on each chromosome involved in this translocation have been identified as the transcription factor-encoding genes PAX3 and FKHR. The NH2-terminal paired box and homeodomain DNA-binding domains of PAX3 are fused in frame to COOH-terminal regions of the chromosome 13-derived FKHR gene, a novel member of the forkhead DNA-binding domain family. To determine the role of the fusion protein in transcriptional regulation and oncogenesis, we identified the PAX3-FKHR fusion protein and characterized its function(s) as a transcription factor relative to wild-type PAX3. Antisera specific to PAX3 and FKHR were developed and used to examine PAX3 and PAX3-FKHR expression in tumor cell lines. Sequential immunoprecipitations with anti-PAX3 and anti-FKHR sera demonstrated expression of a 97-kDa PAX3-FKHR fusion protein in the t(2;13)-positive rhabdomyosarcoma Rh30 cell line and verified that a single polypeptide contains epitopes derived from each protein. The PAX3-FKHR protein was localized to the nucleus in Rh30 cells, as was wild-type PAX3, in t(2;13)-negative A673 cells. In gel shift assays using a canonical PAX binding site (e5 sequence), we found that DNA binding of PAX3-FKHR was significantly impaired relative to that of PAX3 despite the two proteins having identical PAX DNA-binding domains. However, the PAX3-FKHR fusion protein was a much more potent transcriptional activator than PAX3 as determined by transient cotransfection assays using e5-CAT reporter plasmids. The PAX3-FKHR protein may function as an oncogenic transcription factor by enhanced activation of normal PAX3 target genes.

Animals↗

PubMed1995

Inhibition of cellular proliferation by the Wilms' tumor suppressor WT1 is associated with suppression of insulin-like growth factor I receptor gene expression.

We have investigated the regulation of the insulin-like growth factor I receptor (IGF-I-R) gene promoter by the Wilms' tumor suppressor WT1 in intact cells. The levels of endogenous IGF-I-R mRNA and the activity of IGF-I-R gene promoter fragments in luciferase reporter constructs were found to be significantly higher in G401 cells (a Wilms' tumor-derived cell line lacking detectable WT1 mRNA) than in 293 cells (a human embryonic kidney cell line which expresses significant levels of WT1 mRNA). To study whether WT1 could suppress the expression of the endogenous IGF-I-R gene, WT1-negative G401 cells were stably transfected with a WT1 expression vector. Expression of WT1 mRNA in G401 cells resulted in a significant decrease in the rate of cellular proliferation, which was associated with a reduction in the levels of IGF-I-R mRNA, promoter activity, and ligand binding and with a reduction in IGF-I-stimulated cellular proliferation, thymidine incorporation, and anchorage-independent growth. These data suggest that a major aspect of the action of the WT1 tumor suppressor is the repression of IGF-I-R gene expression.

Cell Division↗

PubMed1995

Repression of Pax-2 by WT1 during normal kidney development.

The developmental, regulatory gene Pax-2 is activated during early kidney morphogenesis and repressed in mature renal epithelium. Persistent Pax-2 expression is also observed in a variety of kidney tumors. Yet, little is known about the signals regulating this transient expression pattern in the developing kidney. We have examined the spatial and temporal expression patterns of Pax-2 and the Wilm's tumor suppresser protein WT1 with specific antibodies in developing mouse kidneys. A marked increase in WT1 protein levels coincided precisely with down-regulation of the Pax-2 gene in the individual precursor cells of the visceral glomerular epithelium, suggesting a direct effect of the WT1 repressor protein on Pax-2 regulatory elements. To examine whether WT1 could directly repress Pax-2 transcription, binding of WT1 to three high affinity sites in the 5' untranslated Pax-2 leader sequence was demonstrated by DNAseI footprinting analysis. Furthermore, co-transfection assays using CAT reporter constructs under the control of Pax-2 regulatory sequences demonstrated WT1-dependent transcriptional repression. These three WT1 binding sites were also able to repress transcription, in a WT1-dependent manner, when inserted between a heterologous promoter and the reporter gene. The data indicate that Pax-2 is a likely target gene for WT1 and suggest a direct link, at the level of transcriptional regulation, between a developmental control gene, active in undifferentiated and proliferating cells, and a known tumor suppressor gene.

Animals↗

PubMed1995

Wilms' tumor 1 susceptibility (WT1) gene products are selectively expressed in malignant mesothelioma.

The distinction between malignant mesothelioma and other neoplastic processes involving the pleura is difficult, partly due to the lack of specific markers expressed on mesothelioma. Because of evidence suggesting that the Wilms' tumor susceptibility gene (WT1), unlike other tumor suppressor genes, is restricted mostly to mesenchymally derived tissues, we hypothesized that the WT1 gene products could serve as a potential marker for mesothelioma. The expression of WT1 mRNA was analyzed in 19 malignant mesothelioma cell lines and 9 tumors and compared with the expression of WT1 in 10 non-small cell lung cancer lines and 9 lung cancer specimens. WT1 mRNA was detectable by Northern analysis in 16 of 19 mesothelioma cell lines and in 5 of 8 malignant mesothelioma tumors. In contrast, WT1 mRNA was not detected by Northern analysis in non-small cell lung cancer lines or carcinomas. Immunoprecipitation with an anti-WT1 monoclonal antibody showed that a 52- to 54-kd protein was present in 4 mesothelioma cell lines. Immunostaining with this antibody localized the WT1 protein to the nucleus in two mesothelioma lines and in 20 of 21 mesothelioma tumors examined. This distinctive pattern of nuclear immunoreactivity was absent in 26 non-mesothelioma tumors involving the lung, including 20 non-small cell lung carcinomas. The detection of WT1 mRNA or protein may thus provide a specific molecular or immunohistochemical marker for differentiation of mesothelioma from other pleural tumors, in particular, adenocarcinoma.

Adult↗

PubMed1994

Targeting DNA-binding drugs to sequence-specific transcription factor.DNA complexes. Differential effects of intercalating and minor groove binding drugs.

Intercalating, minor groove binding, and covalently bonding drugs were evaluated by mobility shift assays for their ability to interfere with transcription factors binding to their respective DNA recognition sequences. The Cys2His2 zinc finger proteins EGR1, WT1, and NIL2A, the basic leucine-zipper protein wbJun/wbFos, and the minor groove binding protein hTBP were chosen as representative transcription factors. Their DNA recognition sites include G/C-rich, mixed, and A/T-rich sequences. The intercalators nogalamycin and hedamycin, and the G/C-specific minor groove binding drug chromomycin A3 were the most potent drugs, preventing transcription factor.DNA complex formation at concentrations less than 1 microM. Similar concentrations of chromomycin A3 disrupted preformed complexes while nogalamycin and hedamycin were 50-fold less potent if proteins were allowed to bind DNA prior to drug treatment. Echinomycin inhibited EGR1.DNA complex formation 50% at 5 microM but had little effect on the formation of NIL2A.DNA complexes. Conversely, doxorubicin was found to inhibit NIL2A complex formation 50% at less than 1 microM, but did not achieve this level of inhibition of EGR1/DNA complex formation even at 50 microM. The A/T-directed minor groove binding drugs, while inhibiting hTBP at submicromolar concentrations, had no effect on either EGR1 or NIL2A.

Anthraquinones↗

PubMed1994

Growth of LLC-PK1 renal cells is mediated by EGR-1 up-regulation of G protein alpha i-2 protooncogene transcription.

The early growth response zinc finger transcription factor (EGR-1) and the heterotrimeric guanine nucleotide binding protein encoded by the protooncogene G alpha i-2 each play pivotal roles in signaling pathways that control cell growth and differentiation. The G alpha i-2 gene 5'-flanking region contains a putative binding site (5'-CGCCCCCGC-3') for EGR-1 that may allow it to be a target gene for EGR-1 mitogenic signaling. We now demonstrate in LLC-PK1 renal cells the temporal expression of EGR-1 protein by immunoblotting and immunocytochemistry coincident with the maximal activation of the G alpha i-2 gene during cell growth. To determine whether G alpha i-2 or EGR-1 influence epithelial cell growth, LLC-PK1 cells were transiently transfected with plasmids encoding cDNAs for G alpha i-2 (pRSV G alpha i-2) or EGR-1 (pRSV EGR-1) driven by a viral Rous sarcoma promoter enhancer to overexpress each protein. Following transfection, cell growth was examined in media containing either 10 or 0.1% fetal bovine serum. Only cells transfected with plasmids encoding G alpha i-2 and EGR-1 had growth rates greater than that of serum replete cohorts. To assess whether EGR-1 was contributing to the transcriptional activation of the G alpha i-2 gene, cells were cotransfected with pRSV EGR-1 and plasmids encoding firefly luciferase reporter genes fused to 5'-flanking areas of the G alpha i-2 gene containing either the EGR-1 binding site or a mutated EGR-1 binding site (5'-AAAAACCGC-3'). A 320% enhancement of G alpha i-2 transcription was found only in LLC-PK1 cells following their transfection with plasmids that contained both the EGR-1 binding site and overexpressed EGR-1 protein. Utilizing mobility shift assays, which compared nuclear extracts from cells before and after cell polarization, a probe containing the EGR-1 motif detected induced nuclear protein complexes during transcriptional activation of the G alpha i-2 gene. An anti-EGR-1 antibody specifically retarded the mobility of the induced nuclear complexes, indicating that the EGR-1 protein was a component of these complexes. These data provide direct evidence for a novel mitogenic signaling pathway coupling proximal signaling events that activate EGR-1 gene expression to a target protooncogene G alpha i-2 that is participatory for growth and differentiation in renal cells.

Animals↗

PubMed1994

Effects of minor groove binding drugs on the interaction of TATA box binding protein and TFIIA with DNA.

TBP (TATA box binding protein), a general transcription factor required for proper initiation of gene expression by RNA polymerase II, and minor groove binding drugs (MGBs) both interact with DNA within the minor groove at AT sites. This study has evaluated MGBs as inhibitors of DNA/TBP complex formation by gel mobility shift assays. Our results demonstrate that reversible MGBs (DAPI, distamycin A, Hoechst 33258, and netropsin) are effective inhibitors of the formation of DNA/TBP complex and that distamycin A is the most potent (0.16 microM inhibits TBP complex formation by 50%). CC-1065, a drug that covalently binds to DNA in the minor groove, is even more active than distamycin A (0.00085 microM inhibits TBP complex formation by 50%). Significantly more CC-1065 (0.009 microM) is required to break up preformed DNA/TBP complex compared to the drug concentration needed to prevent complex formation. In comparison, the order of drug addition has little influence on the ability of reversible MGBs to disrupt DNA/TBP complex. In the presence of TFIIA, a factor that enhances TBP association with DNA, greater drug concentrations (distamycin A and CC-1065, respectively) are needed to disrupt a preformed complex of DNA/TBP/TFIIA. In comparison to MGBs, drugs capable of binding to DNA by intercalation are generally weaker at blocking TBP complex formation except for hedamycin, which can intercalate and irreversibly bind to DNA and is as effective as reversible MGBs.

Base Sequence↗

PubMed1994

Krüppel-associated boxes are potent transcriptional repression domains.

The Krüppel-associated box (KRAB) is a highly conserved, 75-aa region containing two predicted amphipathic alpha-helices. The KRAB domain is present in the amino-terminal regions of more than one-third of all Krüppel-class Cys2His2 zinc finger proteins and is conserved from yeast to man; however, its function is unknown. Here it is shown that the KRAB domain functions as a DNA binding-dependent transcriptional repressor when fused to a heterologous DNA-binding domain from the yeast GAL4 protein. A 45-aa segment containing one of the predicted KRAB amphipathic helices was necessary and sufficient for repression. Amino acid substitutions in the predicted helix abolished the repression function. These results assign a function, transcriptional repression, to the highly conserved KRAB box and define a minimal repression domain which may aid in identifying mechanisms of repression.

3T3 Cells↗

PubMed1994

Transcriptional repression of the insulin-like growth factor I receptor (IGF-I-R) gene by the tumor suppressor WT1 involves binding to sequences both upstream and downstream of the IGF-I-R gene transcription start site.

The insulin-like growth factor-I receptor (IGF-I-R) has been implicated in the etiology and/or progression of Wilms' tumor, a pediatric malignancy of the kidney that is often associated with deletion or mutation of the WT1 tumor suppressor gene. The expression of the IGF-I-R gene is increased in Wilms' tumor as compared with normal kidney tissue. Furthermore, the levels of IGF-I-R mRNA in individual tumors have been shown to be inversely correlated to the levels of WT1 mRNA, suggesting that the expression of the IGF-I-R gene is under the negative control of WT1. The activity of an IGF-I-R promoter/luciferase construct in Chinese hamster ovary cells was reduced by cotransfection of a WT1 expression vector. An analysis of various reporter constructs containing different portions of the IGF-I-R 5'-flanking and 5'-untranslated regions suggested that the effect of WT1 depends on the number of WT1 binding sites present, with sites located both upstream and downstream of the IGF-I-R transcription start site involved in mediating this effect. Using the purified zinc finger domain of WT1 in gel retardation and DNase I footprinting assays, we mapped five sites in the 5'-flanking and six sites in the 5'-untranslated regions that were involved in WT1 binding. In addition, the initiator element of the IGF-I-R gene contains a sequence that binds WT1. Thus, the repression of IGF-I-R promoter activity by the WT1 tumor suppressor gene product involves multiple interactions of its zinc finger domain with WT1 binding sites located both 5' and 3' of the transcription initiation site.

Alternative Splicing↗

PubMed1994

RNA editing in the Wilms' tumor susceptibility gene, WT1.

Rat kidney WT1 cDNAs contain either a thymidine or a cytosine residue at position 839. Genomic WT1 DNA contains only T839. To explain these results, we propose the WT1 transcript undergoes RNA editing in which U839 is converted to C, resulting in the replacement of leucine 280 in WT1 by proline. RNA editing at the same nucleotide was observed in WT1 cDNAs from human testis. In functional assays, the WT1-leucine280 polypeptide repressed the EGR-1 promoter in in vitro assays approximately 30% more efficiently than WT1-proline. Edited WT1-C839 mRNA was barely detectable in neonatal kidney, whereas adult rat kidneys contained both U839 and C839-WT1 mRNA, suggesting a role for the two protein isoforms in growth and differentiation.

Animals↗

PubMed1994

The Wilms' tumor suppressor gene WT1 is negatively autoregulated.

The Wilms' tumor suppressor gene WT1 encodes a zinc-finger DNA-binding protein that functions as a transcriptional repressor. WT1 is expressed in a dramatic spatial and temporal pattern during kidney development and is thought to be critical during mesenchymal-epithelial conversion. The WT1 protein bound multiple sites in the WT1 promoter and functioned as a powerful transcriptional repressor of its gene in vivo (> 50-fold). The WT1 protein carrying an NH2-terminal 17-amino acid insertion and a 3-amino acid insertion (KTS) between zinc fingers 3 and 4, arising from the most abundant of four alternatively spliced transcripts, was the most powerful repressor. Of importance, a subset of WT1-binding sites differs from the Egr-1 consensus sequence, which has been shown to bind one splice variant of the WT1 protein (WT1(-KTS)). We characterized two of these sites and show that they bind both -KTS and +KTS forms of the WT1 zinc-finger protein and can confer repression on a heterologous promoter construct. Our data demonstrate that WT1, in addition to its known effects on insulin-like growth factor II, platelet-derived growth factor A, and Pax-2 transcription, is a powerful repressor of its own gene. These observations emphasize its critical role as a transcriptional regulatory protein during normal kidney development.

Base Sequence↗

PubMed1994

Novel oncogenic mutations in the WT1 Wilms' tumor suppressor gene: a t(11;22) fuses the Ewing's sarcoma gene, EWS1, to WT1 in desmoplastic small round cell tumor.

These studies suggest that the WT1 tumor suppressor gene, originally identified as a recessive oncogene in Wilms' tumors, is capable of sustaining a gain-of-function mutation which results in its contribution to a completely different disease entity: desmoplastic small round cell tumor. Two independent biochemical functions of WT1, DNA-binding activity and mode of transcriptional regulation, are altered as a consequence of the chromosomal translocation and fusion with EWS. The fusion of EWS and WT1 genes in DSRCT thus provides a unique paradigm for a means by which different alterations of transcription factor function can lead to diverse oncogenic processes.

Amino Acid Sequence↗

PubMed1994

Characterization of the DNA-binding properties of the myeloid zinc finger protein MZF1: two independent DNA-binding domains recognize two DNA consensus sequences with a common G-rich core.

The myeloid zinc finger gene 1, MZF1, encodes a transcription factor which is expressed in hematopoietic progenitor cells that are committed to myeloid lineage differentiation. MZF1 contains 13 C2H2 zinc fingers arranged in two domains which are separated by a short glycine- and proline-rich sequence. The first domain consists of zinc fingers 1 to 4, and the second domain is formed by zinc fingers 5 to 13. We have determined that both sets of zinc finger domains bind DNA. Purified, recombinant MZF1 proteins containing either the first set of zinc fingers or the second set were prepared and used to affinity select DNA sequences from a library of degenerate oligonucleotides by using successive rounds of gel shift followed by PCR amplification. Surprisingly, both DNA-binding domains of MZF1 selected similar DNA-binding consensus sequences containing a core of four or five guanine residues, reminiscent of an NF-kappa B half-site: 1-4, 5'-AGTGGGGA-3'; 5-13, 5'-CGGGnGAGGGGGAA-3'. The full-length MZF1 protein containing both sets of zinc finger DNA-binding domains recognizes synthetic oligonucleotides containing either the 1-4 or 5-13 consensus binding sites in gel shift assays. Thus, we have identified the core DNA consensus binding sites for each of the two DNA-binding domains of a myeloid-specific zinc finger transcription factor. Identification of these DNA-binding sites will allow us to identify target genes regulated by MZF1 and to assess the role of MZF1 as a transcriptional regulator of hematopoiesis.

Amino Acid Sequence↗