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Gene Review

SF1  -  splicing factor 1

Homo sapiens

Synonyms: BBP, D11S636, MBBP, Mammalian branch point-binding protein, Splicing factor 1, ...
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Disease relevance of SF1

  • Gonadal dysgenesis may be isolated, as in the case of SRY mutations, or associated with abnormal development of other organs, such as bone or adrenals, consistent with the spatial expression profile of the disrupted genes (SOX9 or SF1) [1].
  • New mutations in SF1, DAX1 and GnRHR genes were identified in three Brazilian patients with hypogonadism [2].
  • Mutations of SF-1 gene cause metabolic disorders like obesity in both human and mice [3].
  • To investigate how the KH domain of SF1/mBBP recognizes the BPS in conjunction with U2AF and possibly other proteins, we constructed a transcriptional reporter system utilizing human immunodeficiency virus type 1 Tat fusion proteins and examined the RNA-binding specificity of the complex using KH domain and RNA-binding site mutants [4].
  • One of these cDNAs encodes ZFM1, a protein previously identified at the locus linked to multiple endocrine neoplasia type 1 (MEN1) and as presplicing factor SF1 [5].

Psychiatry related information on SF1

  • We then propose that SF-1 may be a key transcriptional regulator of AMHRII gene expression during early human development [6].
  • SF-1 message was also found in adrenal and in the periventricular region of the preoptic area and diencephalon, but there was no apparent sex bias in these tissues at any stage examined [7].
  • Since its Km for actin is similar to that of tryptic SF1(A2), it may be concluded that changes in the affinity of SF1 for actin induced by trypsin [Botts, J., Muhlrad, A., Takashi, R., & Morales, M. F. (1982) Biochemistry 21, 6903-6905] are not dependent on the presence of the associated alkali light chain [8].

High impact information on SF1


Chemical compound and disease context of SF1

  • We identified a new heterozygous SF1 gene mutation, C16X, in a 46, XY patient showing gonadal dysgenesis with normal adrenal function: low basal levels of AMH and testosterone (T), weak T response to hCG, hypoplastic testes with abundant seminiferous tubules but rare germ cells [11].
  • Three cyclic peptides, BBP, an organ specific localization peptide; RGD, an inhibitor of platelet aggregation; and CDR-H3/C2, which inhibits HIV-1 replication, were isolated using the two-intein system [12].
  • Between 1998 and 2000 an Expert Panel convened by the National Toxicology Program's Center for the Evaluation of Risks to Human Reproduction (NTP-CERHR) reviewed information related to the developmental and reproductive toxicity of seven phthalate esters; DBP, BBP, DnHP, DEHP, DnOP, DINP, and DIDP [13].

Biological context of SF1

  • Phosphorylation of SF1 also occurs in cultured neuronal cells and is increased on Ser20 in response to a cGMP analogue [14].
  • A critical protein in NMD is Upf1p, which belongs to the helicase super family 1 (SF1), and is thought to utilize the energy of ATP hydrolysis to promote transitions in the structure of RNA or RNA-protein complexes [15].
  • Mutational analysis of this new distal SF-1 site and the previously identified proximal SF-1 site showed that both are necessary for transcriptional activation [16].
  • We demonstrated for the first time that the mFSHR promoter possesses functional SF-1 binding sites and thus belongs to the group of SF-1-regulated genes [17].
  • GATA-4/SF-1 synergism was the result of a direct protein-protein interaction mediated through the zinc finger region of GATA-4 [18].

Anatomical context of SF1

  • Phosphorylation of splicing factor SF1 on Ser20 by cGMP-dependent protein kinase regulates spliceosome assembly [14].
  • Two active polysaccharide fractions (SF1 and SF2) purified from dried safflower petals (Carthamus tinctorius L.) stimulated the synthesis of various cytokines by peritoneal macrophages [19].
  • The cellular levels of SF-1 mRNA and protein closely correlated in various steroidogenic cell lines with activity of the transfected mFSHR promoter/luciferase reporter construct carrying the distal activator domain [17].
  • The zinc finger transcription factor GATA-4 and nuclear receptor SF-1 are early markers of Sertoli cells that have been shown to regulate MIS transcription [18].
  • Northern blot analyses of peripheral tissues revealed high hSF-1 mRNA expression in the adrenal cortex and the gonads, but no hSF-1 mRNA was detected in the placenta [20].

Associations of SF1 with chemical compounds

  • ZFM1 was shown to interact with and repress transcription from the glycine, glutamine, serine, and threonine-rich transcription activation domain of the sea urchin transcription factor, stage-specific activator protein (SSAP) [21].
  • Here we report that ZFM1 also interacts with EWS in both two-hybrid assays and glutathione S-transferase pull-down experiments [21].
  • The results suggest that SF-1 haploinsufficiency can selectively impair testicular development and permit the biosynthesis of AMH and testosterone in dysgenetic testes and the production of gonadotropins in pituitary gonadotropes [22].
  • The structure of the C-terminal RRM (RRM3) of human U2AF(65) complexed to an N-terminal peptide of SF1 reveals an extended negatively charged helix A and an additional helix C [23].
  • All SF1 cDNAs identified encode proteins with a common N-terminal half that contains two structural motifs implicated in RNA binding (an hnRNP K homology [KH] domain and a zinc knuckle), but the proteins differ in the length of a proline-rich region and have distinct C-termini [24].

Physical interactions of SF1

  • Our results show that SF1 interacts strongly with human U2AF65, and that SF1 is a bona fide E complex component [25].
  • The region on EWS which interacts with ZFM1 maps to 37 amino acids within its NTD [21].

Regulatory relationships of SF1


Other interactions of SF1

  • These results suggest a new role for PKG in mammalian pre-mRNA splicing by regulating in a phosphorylation-dependent manner the association of SF1 with U2AF65 and spliceosome assembly [14].
  • Using semiquantitative RT-PCR analysis the upregulation of the transforming growth factor-alpha, integrin alpha 6 and ZFM 1 transcription factor in mature DCs was confirmed in samples from four different individuals [28].
  • A protein that interacted directly with CA150 WW1 and WW2 was identified as the splicing-transcription factor SF1 [29].
  • These data suggest that ZFM1 might be a candidate for mutations that cause MEN1 [30].
  • The KH domain of SF1 is embedded in a 160-amino acid sequence that is shared with human Sam68, a target of Src during mitosis, as well as Caenorhabditis elegans GLD-1 and mouse Qkl, both of which play roles during cellular differentiation [24].

Analytical, diagnostic and therapeutic context of SF1

  • In situ hybridization studies confirmed the strong expression of hSF-1 mRNA in adrenal cortex, ovary, testis, and the spleen, primarily within reticuloendothelial cells [20].
  • Sequence analysis was performed for all the seven exons of SF-1, revealing a heterozygous single base pair deletion at exon 2 (18delC) that is predicted to cause a frameshift at the sixth codon and resultant termination at the 74th codon [22].
  • Competitive mobility shift assays using either alphaT3-1 nuclear extract or recombinant SF-1 protein clearly indicated that SF-1 is able to interact specifically with this GSE element positioned at -134 [31].
  • SF1, SF2, and SF4B appear to be required for cleavage of the pre-mRNA at the 5' splice site and lariat formation, whereas SF3 and SF4A are only required for cleavage at the 3' splice site and exon ligation [32].
  • Deletion and site-directed mutagenesis localized a novel SF-1 regulatory element (TCA GGGCCA; -137 to -129) adjacent to a variant cAMP-response element (CRE; -120 to -114) [33].


  1. Anomalies of human sexual development: clinical aspects and genetic analysis. Vilain, E. Novartis Found. Symp. (2002) [Pubmed]
  2. Clinical and molecular analysis of human reproductive disorders in Brazilian patients. Latronico, A.C., Costa, E.M., Domenice, S., Correa, R.V., Kohek, M.B., Arnhold, I.J., Mendonca, B.B. Braz. J. Med. Biol. Res. (2004) [Pubmed]
  3. The Gly146Ala variation in human SF-1 gene: its association with insulin resistance and type 2 diabetes in Chinese. Liu, W., Liu, M., Fan, W., Nawata, H., Yanase, T. Diabetes Res. Clin. Pract. (2006) [Pubmed]
  4. Recognition of RNA branch point sequences by the KH domain of splicing factor 1 (mammalian branch point binding protein) in a splicing factor complex. Peled-Zehavi, H., Berglund, J.A., Rosbash, M., Frankel, A.D. Mol. Cell. Biol. (2001) [Pubmed]
  5. Human ZFM1 protein is a transcriptional repressor that interacts with the transcription activation domain of stage-specific activator protein. Zhang, D., Childs, G. J. Biol. Chem. (1998) [Pubmed]
  6. Steroidogenic factor-1 regulates transcription of the human anti-müllerian hormone receptor. Barbara, P.S., Moniot, B., Poulat, F., Boizet, B., Berta, P. J. Biol. Chem. (1998) [Pubmed]
  7. Developmental expression of steroidogenic factor 1 in a turtle with temperature-dependent sex determination. Fleming, A., Wibbels, T., Skipper, J.K., Crews, D. Gen. Comp. Endocrinol. (1999) [Pubmed]
  8. Effect of tryptic cleavage on the stability of myosin subfragment 1. Isolation and properties of the severed heavy-chain subunit. Burke, M., Kamalakannan, V. Biochemistry (1985) [Pubmed]
  9. Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1. Krylova, I.N., Sablin, E.P., Moore, J., Xu, R.X., Waitt, G.M., MacKay, J.A., Juzumiene, D., Bynum, J.M., Madauss, K., Montana, V., Lebedeva, L., Suzawa, M., Williams, J.D., Williams, S.P., Guy, R.K., Thornton, J.W., Fletterick, R.J., Willson, T.M., Ingraham, H.A. Cell (2005) [Pubmed]
  10. Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression. Nachtigal, M.W., Hirokawa, Y., Enyeart-VanHouten, D.L., Flanagan, J.N., Hammer, G.D., Ingraham, H.A. Cell (1998) [Pubmed]
  11. Gonadal dysgenesis without adrenal insufficiency in a 46, XY patient heterozygous for the nonsense C16X mutation: a case of SF1 haploinsufficiency. Mallet, D., Bretones, P., Michel-Calemard, L., Dijoud, F., David, M., Morel, Y. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  12. The cyclization and polymerization of bacterially expressed proteins using modified self-splicing inteins. Evans, T.C., Benner, J., Xu, M.Q. J. Biol. Chem. (1999) [Pubmed]
  13. NTP center for the evaluation of risks to human reproduction reports on phthalates: addressing the data gaps. McKee, R.H., Butala, J.H., David, R.M., Gans, G. Reprod. Toxicol. (2004) [Pubmed]
  14. Phosphorylation of splicing factor SF1 on Ser20 by cGMP-dependent protein kinase regulates spliceosome assembly. Wang, X., Bruderer, S., Rafi, Z., Xue, J., Milburn, P.J., Krämer, A., Robinson, P.J. EMBO J. (1999) [Pubmed]
  15. Structural and functional insights into the human Upf1 helicase core. Cheng, Z., Muhlrad, D., Lim, M.K., Parker, R., Song, H. EMBO J. (2007) [Pubmed]
  16. Endogenous expression of Müllerian inhibiting substance in early postnatal rat sertoli cells requires multiple steroidogenic factor-1 and GATA-4-binding sites. Watanabe, K., Clarke, T.R., Lane, A.H., Wang, X., Donahoe, P.K. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  17. The promoter of murine follicle-stimulating hormone receptor: functional characterization and regulation by transcription factor steroidogenic factor 1. Levallet, J., Koskimies, P., Rahman, N., Huhtaniemi, I. Mol. Endocrinol. (2001) [Pubmed]
  18. Transcription factor GATA-4 enhances Müllerian inhibiting substance gene transcription through a direct interaction with the nuclear receptor SF-1. Tremblay, J.J., Viger, R.S. Mol. Endocrinol. (1999) [Pubmed]
  19. Safflower polysaccharides activate the transcription factor NF-kappa B via Toll-like receptor 4 and induce cytokine production by macrophages. Ando, I., Tsukumo, Y., Wakabayashi, T., Akashi, S., Miyake, K., Kataoka, T., Nagai, K. Int. Immunopharmacol. (2002) [Pubmed]
  20. Steroidogenic factor 1 messenger ribonucleic acid expression in steroidogenic and nonsteroidogenic human tissues: Northern blot and in situ hybridization studies. Ramayya, M.S., Zhou, J., Kino, T., Segars, J.H., Bondy, C.A., Chrousos, G.P. J. Clin. Endocrinol. Metab. (1997) [Pubmed]
  21. The transcriptional repressor ZFM1 interacts with and modulates the ability of EWS to activate transcription. Zhang, D., Paley, A.J., Childs, G. J. Biol. Chem. (1998) [Pubmed]
  22. Testicular dysgenesis without adrenal insufficiency in a 46,XY patient with a heterozygous inactive mutation of steroidogenic factor-1. Hasegawa, T., Fukami, M., Sato, N., Katsumata, N., Sasaki, G., Fukutani, K., Morohashi, K., Ogata, T. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  23. Structural basis for the molecular recognition between human splicing factors U2AF65 and SF1/mBBP. Selenko, P., Gregorovic, G., Sprangers, R., Stier, G., Rhani, Z., Krämer, A., Sattler, M. Mol. Cell (2003) [Pubmed]
  24. Mammalian splicing factor SF1 is encoded by variant cDNAs and binds to RNA. Arning, S., Grüter, P., Bilbe, G., Krämer, A. RNA (1996) [Pubmed]
  25. Cross-intron bridging interactions in the yeast commitment complex are conserved in mammals. Abovich, N., Rosbash, M. Cell (1997) [Pubmed]
  26. ZFM1/SF1 mRNA in rat and gerbil brain after global ischaemia. Covini, N., Tamburin, M., Consalez, G., Salvati, P., Benatti, L. Eur. J. Neurosci. (1999) [Pubmed]
  27. Splicing factor Tra2-beta1 is specifically induced in breast cancer and regulates alternative splicing of the CD44 gene. Watermann, D.O., Tang, Y., Zur Hausen, A., Jäger, M., Stamm, S., Stickeler, E. Cancer Res. (2006) [Pubmed]
  28. Expression of renin-angiotensin system genes in immature and mature dendritic cells identified using human cDNA microarray. Lapteva, N., Nieda, M., Ando, Y., Ide, K., Hatta-Ohashi, Y., Dymshits, G., Ishikawa, Y., Juji, T., Tokunaga, K. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  29. The transcription elongation factor CA150 interacts with RNA polymerase II and the pre-mRNA splicing factor SF1. Goldstrohm, A.C., Albrecht, T.R., Suñé, C., Bedford, M.T., Garcia-Blanco, M.A. Mol. Cell. Biol. (2001) [Pubmed]
  30. Isolation and characterization of a novel gene encoding nuclear protein at a locus (D11S636) tightly linked to multiple endocrine neoplasia type 1 (MEN1). Toda, T., Iida, A., Miwa, T., Nakamura, Y., Imai, T. Hum. Mol. Genet. (1994) [Pubmed]
  31. Steroidogenic factor-1 interacts with a gonadotrope-specific element within the first exon of the human gonadotropin-releasing hormone receptor gene to mediate gonadotrope-specific expression. Ngan, E.S., Cheng, P.K., Leung, P.C., Chow, B.K. Endocrinology (1999) [Pubmed]
  32. Multiple factors including the small nuclear ribonucleoproteins U1 and U2 are necessary for pre-mRNA splicing in vitro. Krainer, A.R., Maniatis, T. Cell (1985) [Pubmed]
  33. Synergistic activation of the inhibin alpha-promoter by steroidogenic factor-1 and cyclic adenosine 3',5'-monophosphate. Ito, M., Park, Y., Weck, J., Mayo, K.E., Jameson, J.L. Mol. Endocrinol. (2000) [Pubmed]
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