skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: The heterodimeric structure of heterogeneous nuclear ribonucleoprotein C1/C2 dictates 1,25-dihydroxyvitamin D-directed transcriptional events in osteoblasts

Journal Article · · Bone Research
 [1];  [2];  [2];  [2];  [2];  [2];  [2]
  1. Univ. of California, Los Angeles, CA (United States). Orthopaedic Hospital Research Center and Dept. of Orthopaeic Surgery; Mount Desert Island Biological Laboratory, Bar Harbor, ME (United States). Dept. of Regenerative Biology and Medicine
  2. Univ. of California, Los Angeles, CA (United States). Orthopaedic Hospital Research Center and Dept. of Orthopaeic Surgery
+ Show Author Affiliations

Heterogeneous nuclear ribonucleoprotein (hnRNP) C plays a key role in RNA processing but also exerts a dominant negative effect on responses to 1,25-dihydroxyvitamin D (1,25(OH)2D) by functioning as a vitamin D response element-binding protein (VDRE-BP). hnRNPC acts a tetramer of hnRNPC1 (huC1) and hnRNPC2 (huC2), and organization of these subunits is critical to in vivo nucleic acid-binding. Overexpression of either huC1 or huC2 in human osteoblasts is sufficient to confer VDRE-BP suppression of 1,25(OH)2D-mediated transcription. However, huC1 or huC2 alone did not suppress 1,25(OH)2D-induced transcription in mouse osteoblastic cells. By contrast, overexpression of huC1 and huC2 in combination or transfection with a bone-specific polycistronic vector using a ‘‘self-cleaving’’ 2A peptide to co-express huC1/C2 suppressed 1,25D-mediated induction of osteoblast target gene expression. Structural diversity of hnRNPC between human/NWPs and mouse/rat/rabbit/dog was investigated by analysis of sequence variations within the hnRNP CLZ domain. The predicted loss of distal helical function in hnRNPC from lower species provides an explanation for the altered interaction between huC1/C2 and their mouse counterparts. These data provide new evidence of a role for hnRNPC1/C2 in 1,25(OH)2D-driven gene expression, and further suggest that species-specific tetramerization is a crucial determinant of its actions as a regulator of VDR-directed transactivation.

Research Organization:
Univ. of California, Los Angeles, CA (United States)
Sponsoring Organization:
USDOE; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Institutes of Health (NIH)
Grant/Contract Number:
5R01AR037399
OSTI ID:
1623742
Journal Information:
Bone Research, Vol. 2, Issue 1; ISSN 2095-6231
Publisher:
Springer NatureCopyright Statement
Country of Publication:
United States
Language:
English

References (41)

CHARMM: the biomolecular simulation program text January 2009
Functional Characterization of Heterogeneous Nuclear Ribonuclear Protein C1/C2 in Vitamin D Resistance journal December 2006
Gene targeting by the vitamin D response element binding protein reveals a role for vitamin D in osteoblast mTOR signaling journal November 2010
Solution Structure of the Symmetric Coiled Coil Tetramer Formed by the Oligomerization Domain of hnRNP C: Implications for Biological Function journal July 2005
Vitamin D: A new player in the world of mTOR signaling journal June 2011
High Cleavage Efficiency of a 2A Peptide Derived from Porcine Teschovirus-1 in Human Cell Lines, Zebrafish and Mice journal April 2011
Vitamin D receptor signaling mechanisms: Integrated actions of a well-defined transcription factor journal February 2013
Scalable molecular dynamics with NAMD journal January 2005
Molecular Mechanisms of Vitamin D Action journal July 2012
Molecular cloning of cDNA for the nuclear ribonucleoprotein particle C proteins: a conserved gene family. journal April 1986
The Amber biomolecular simulation programs journal January 2005
High-efficiency transformation of mammalian cells by plasmid DNA journal August 1987
Heterogeneous nuclear ribonucleoprotein (hnRNP) binding to hormone response elements: A cause of vitamin D resistance journal April 2003
Regulation of urokinase receptor mRNA stability by hnRNP C in lung epithelial cells journal April 2005
An antiparallel four-helix bundle orients the high-affinity RNA binding sites in hnRNP C: a mechanism for RNA chaperonin activity journal January 2001
A seven-helix coiled coil journal October 2006
The Vitamin D Receptor: New Paradigms for the Regulation of Gene Expression by 1,25-Dihydroxyvitamin D3 journal February 2012
hnRNP Proteins and the Biogenesis of mRNA journal June 1993
Structure and Function of Nuclear and Cytoplasmic Ribonucleoprotein Particles journal November 1986
Primary structure of human nuclear ribonucleoprotein particle C proteins: conservation of sequence and domain structures in heterogeneous nuclear RNA, mRNA, and pre-rRNA-binding proteins journal May 1987
Primary structure differences between proteins C1 and C2 of HeLa 40S nuclear ribonucleoprotein particles journal January 1989
A transient three-plasmid expression system for the production of high titer retroviral vectors journal January 1995
Response element binding proteins and intracellular vitamin D binding proteins: novel regulators of vitamin D trafficking, action and metabolism journal May 2004
hnRNP C Tetramer Measures RNA Length to Classify RNA Polymerase II Transcripts for Export journal March 2012
Hormone response element binding proteins: Novel regulators of vitamin D and estrogen signaling journal March 2011
Heterogeneous nuclear ribonucleoprotein C1/C2, MeCP1, and SWI/SNF form a chromatin remodeling complex at the  -globin locus control region journal October 2005
Use of the 2A sequence from foot-and-mouth disease virus in the generation of retroviral vectors for gene therapy journal February 1999
RNA binding specificity of hnRNP A1: significance of hnRNP A1 high-affinity binding sites in pre-mRNA splicing. journal March 1994
Heterogeneous ribonucleoprotein C displays a repressor activity mediated by T-cell intracellular antigen-1-related/like protein to modulate Fas exon 6 splicing through a mechanism involving Hu antigen R journal August 2010
High-efficiency transformation of mammalian cells by plasmid DNA. journal August 1987
CHARMM: The biomolecular simulation program journal July 2009
The Vitamin D Receptor: New Paradigms for the Regulation of Gene Expression by 1,25-Dihydroxyvitamin D3 journal June 2010
Conserved structures and diversity of functions of RNA-binding proteins journal July 1994
Primary structure of human nuclear ribonucleoprotein particle C proteins: conservation of sequence and domain structures in heterogeneous nuclear RNA, mRNA, and pre-rRNA-binding proteins. journal May 1987
Specific binding of heterogeneous ribonucleoprotein particle protein K to the human c-myc promoter, in vitro. journal August 1993
Novel regulators of vitamin D action and metabolism: Lessons learned at the Los Angeles zoo: Regulators of Vitamin D Action and Metabolism journal November 2002
The Vitamin D Response Element-binding Protein journal November 2000
The nuclear vitamin D receptor controls the expression of genes encoding factors which feed the “Fountain of Youth” to mediate healthful aging journal July 2010
The roles of heterogeneous nuclear ribonucleoproteins in tumour development and progression journal April 2006
hnRNP complexes: composition, structure, and function journal June 1999
Vitamin D and gonadal steroid-resistant New World primate cells express an intracellular protein which competes with the estrogen receptor for binding to the estrogen response element. journal February 1997

Cited By (4)

DNA Damage-Inducible Transcript 4 Is an Innate Surveillant of Hair Follicular Stress in Vitamin D Receptor Knockout Mice and a Regulator of Wound Re-Epithelialization journal November 2016
Exploring vitamin D signalling within skin cancer journal January 2020
New moonlighting functions of mitochondrial cytochrome c in the cytoplasm and nucleus journal October 2019
Proteomic analysis of novel targets associated with the enhancement of TrkA-induced SK-N-MC cancer cell death caused by NGF journal May 2016

Similar Records

Expression of human kinase suppressor of Ras 2 (hKSR-2) gene in HL60 leukemia cells is directly upregulated by 1,25-dihydroxyvitamin D{sub 3} and is required for optimal cell differentiation
Journal Article · Wed Aug 15 00:00:00 EDT 2007 · Experimental Cell Research · OSTI ID:1623742
+1 more
1α,25-dihydroxyvitamin D3 stimulates human SOST gene expression and sclerostin secretion
Journal Article · Tue Jun 23 00:00:00 EDT 2015 · Molecular and Cellular Endocrinology · OSTI ID:1623742
+8 more
Crosstalk between the peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) and the vitamin D receptor (VDR) in human breast cancer cells: PPAR{gamma} binds to VDR and inhibits 1{alpha},25-dihydroxyvitamin D{sub 3} mediated transactivation
Journal Article · Thu Nov 15 00:00:00 EST 2012 · Experimental Cell Research · OSTI ID:1623742
+3 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Cell biology
Biochemistry
Osteoblasts
Transcription