Beverly S. Chilton, Ph.D.
Helicase-like transcriptionfactor (HLTF/Hltf) in reproduction and colon cancer.
For more than 20 years, I’ve explored the fact that prolactin augments the progesterone-dependent increase in transcription of the uteroglobin (SCGB1A1) gene. My search for responsible transcription factors began with the cloning and characterization of RUSH, the alias for rabbit HLTF, and culminated in the characterization of the Jak/RUSH alternative to Jak/STAT signaling in rabbit endometrium. During this time, HLTF was identified as a tumor suppressor silenced by promoter hypermethylation in colon cancer cells. Our murine HLTF ortholog knockout model (Hltf-/-) exhibited significant brain and cardiac defects, persistent hypoglycemia, and perinatal lethality. We are currently pursuing two lines of inquiry.
Project 1: Hltf regulates the structural integrity of the extracellular matrix, and provides the strongest clues to date as to how silencing Hltf benefits tumor growth. Our goal is to define the tumor promoting effect(s) of HLTF silencing in a human colon cancer cell line model and the effects of Hltf silencing in the supporting murine stroma (i.e., field effect) as a model of human disease. Our hypothesis is that tumor cell and/or stromal cell silencing of HLTF promotes a permissive pathway for the invasive growth of colon cancer cells via altered biogenesis of extracellular matrix (ECM) collagen.
Project 2: Hltf regulates placental serotonergic signaling in placenta. Our goal is to define the extent to which the phenotype of the Hltf null pancreas results from fetal, maternal and/or placental sources of serotonin. Our hypothesis is that silencing Hltf down regulates placental serotonin that causes reduced-beta cell mass and insulin production in the fetal pancreas.
- Helmer RA, Martinez-Zaguilán R, Dertien JS, Fulford C, Foreman O, Peiris V, Chilton BS. Helicase-like transcription factor (Hltf) regulates G2/M transition, Wt1/Gata4/Hif-1a cardiac transcription networks, and collagen biogenesis. PLoS One. 2013 Nov 20;8(11):e80461. doi: 10.1371/journal.pone.0080461. eCollection 2013. PubMed
- Helmer RA, Foreman O, Dertien JS, Panchoo M, Bhakta SM, Chilton BS. Role of helicase-like transcription factor (Hltf) in the G2/M transition and apoptosis in brain. PLoS One. 2013Jun24;8(6):e66799. doi:10.1371/journal.pone. 0066799. Print 2013. PubMed
- Helmer RA, Dertien JS, Chilton BS. Prolactin induced Jak2 phosphorylation of RUSHY195. Mol Cell Endocrinol. 2011; 338:79-83. PubMed
- Helmer RA, Panchoo M, Dertien JS, Bhakta SM, Hewetson A, Chilton BS. Prolactin-induced Jak2 phosphorylation of RUSH: a key element in Jak/RUSH signaling. Mol Cell Endocrinol. 2010; 325:143-149. PubMed
- Hewetson, A, Chilton BS. Progesterone-dependent DNA-looping between RUSH/SMARCA3 and Egr-1 mediates repression by c-Rel. Mol Endocrinol. 2008;22:813-822. PubMed
- Hewetson A, Moore SL, Chilton BS. Prolactin signals through RUSH/SMARCA3 in the absence of a physical association with Stat5a. Biol Reprod. 2004;71:1907-1912. PubMed
- Hewetson A, Chilton BS. An Sp1-NF-Y/Progesterone Receptor DNA Binding-dependent Mechanism Regulates Progesterone-induced Transcription of the Rabbit RUSH/SMARCA3 Gene. J Biol Chem. 2003;278:40177-40185. PubMed
- Hewetson, A, Hendrix EC, Mansharamani M, Lee,VH, Chilton BS. Identification of the RUSH consensus-binding site by cyclic amplification and selection of targets: Demonstration that RUSH mediates the ability of prolactin to augment progesterone-dependent gene expression. Mol Endocrinol. 2002;16:2101-2112. PubMed
- Mansharamani M, Hewetson A, Chilton BS. Cloning and characterization of an atypical Type IV P-type ATPase that binds to the RING motif of RUSH transcription factors. J Biol Chem. 2001;276:3641-3649. PubMed
- Mansharamani M, Chilton BS. Prolactin augments progesterone-dependent expression of a nuclear P-type ATPase that associates with the RING domain of RUSH transcription factors in the endometrium. Ann NY Acad Sci. 2000;923:321-324. PubMed
- Chilton BS, Hewetson A, Devine J, Hendrix E, Mansharamani M. Uteroglobin gene transcription, What’s the RUSH? Ann NY Acad Sci. 2000;923:166-180. PubMed
- Rendon A, Hewetson A, Chilton BS, Lee VH. Expression of RUSH transcription factors in developing and adult rabbit gonads. Biol Reprod. 2000;63:156-164. PubMed
- Devine JH, Hewetson A, Lee VH, Chilton BS. After chromatin is SWItched-on can it be RUSHed? Mol Cell Endocrinol. 1999;151:49-56. PubMed
- Doris PA, Oefner PJ, Chilton BS, Hayward-Lester A. Quantitative analysis of gene expression by ion-pair high-performance liquid chromatography. J. Chromatography A. 1998;806:47-60. PubMed
- Chilton BS, Hewetson A. Zinc finger proteins RUSH in where others fear to tread. Biol Reprod. 1998;58:285-294. PubMed
- Hewetson A, Chilton BS. Novel elements in the uteroglobin promoter are a functional target for prolactin signaling. Mol Cell Endocrinol. 1997;136:1-6. PubMed
- Hayward-Lester A, Hewetson A, Oefner PJ, Doris PA, Chilton BS. Cloning, characterization and steroid-dependent posttranscriptional processing of RUSH-1 α & β, two uteroglobin promoter binding proteins. Mol Endocrinol. 1996;10:1335-1349. PubMed
- Kleis-SanFrancisco S, Hewetson A, Chilton BS. Prolactin augments progesterone-dependent uteroglobin gene expression by modulating promoter-binding proteins. Mol Endocrinol. 1993;7:214-223. PubMed
- Chilton BS, Mani SK, Bullock DW. Servomechanism of prolactin and progesterone in regulating uterine gene expression. Mol Endocrinol. 1988;2:1169-1175. PubMed
- Daniel Jr JC, Jetton AE, Chilton BS. Prolactin as a factor in the uterine response to progesterone in rabbits. J Reprod Fert. 1984;72:443-452. PubMed