Positions
- Professor
-
Pathology & Immunology
草榴社区入口
Houston, TX US
- Director of Operations & Membership
-
Center for Drug Discovery
- Member
-
Dan L Duncan Comprehensive Cancer Center
草榴社区入口
Houston, Texas United States
Education
- Ph.D. from University Of Oklahoma College Of Medicine
- 01/1984 - Oklahoma City, OK United States
- B.S. from Missouri Western State University
- 01/1978 - St. Joseph, MO United States
Professional Interests
- Glycobiology
- Secretory Pathway
- Protein Biosynthetic Quality Control
- Conformational Disease
- Alpha1-antitrypsin Deficiency
- Disease Modifiers
- ER Stress and Unfolded Protein Response
- Cell Stress Responses and Cancer Cell Pro-Survival
Professional Statement
Genetic information is inherited as DNA and stored in the nucleus. Despite this important role, the encoded proteins are responsible for performing most of the catalytic and structural functions that take place in living cells. Importantly, protein folding and quality control systems comprise two branches of a post-translational gene expression checkpoint. Their contribution to disease pathogenesis is illustrated by their conspicuous involvement in numerous loss-of-function and gain-of-toxic function disorders.Arguably, protein biosynthetic quality control is best understood in the secretory pathway where the processing of asparagine-linked oligosaccharides functions to orchestrate the elimination of numerous aberrant glycoproteins unable to acquire structural maturation. In particular, we have discovered that modification of the asparagine-linked appendage by endoplasmic reticulum mannosidase I (ERManI), in combination with non-native protein structure, is responsible for generating the degradation signal. Importantly, the concentration of ERManI controls the rate of substrate degradation by controlling the rate at which the degradation signal is formed.
However, neither the mechanism by which the ERManI concentration is controlled or its contribution to disease pathogenesis is fully understood. We have begun to dissect this key regulatory pathway and have shown that the ERManI concentration is controlled at both translational and post-translational levels. Furthermore, preliminary data imply that an elevated ERManI concentration plays a protective role against the development of liver disease associated with plasma alpha1-antitrypsin deficiency, presumably by hindering the accumulation of PI Z polymers in the ER of liver hepatocytes. Likewise, an apparent failure to up-regulate the ERManI concentration coincides with the development of the early-onset form of the disorder.
The immediate goals are to further dissect the mechanism of human ERManI regulation and delineate its participation in the etiology of the liver disease. The long term goal is to demonstrate how a core element of the glycoprotein quality control machinery can function as a disease modifier, possible diagnostic marker, and potential site for therapeutic intervention.
Websites
Selected Publications
- Liu Y, Choudhury P, Cabral CM, Sifers RN "." J. Biol. Chem.. 1999 Feb 26;274(9):5861-7. Pubmed PMID:
- Cabral CM, Choudhury P, Liu Y, Sifers RN "." J. Biol. Chem.. 2000 Aug 11;275(32):25015-22. Pubmed PMID:
- Cabral CM, Liu Y, Sifers RN "." Trends Biochem. Sci.. 2001 Oct;26(10):619-24. Pubmed PMID:
- Cabral CM, Liu Y, Moremen KW, Sifers RN "." Mol. Biol. Cell. 2002 Aug;13(8):2639-50. Pubmed PMID:
- Sifers RN "." Science. 2003 Feb 28;299:1330-1331. Pubmed PMID:
- Wu Y, Swulius MT, Moremen KW, Sifers RN "." Proc. Natl. Acad. Sci. U.S.A.. 2003 Jul 8;100(14):8229-34. Pubmed PMID:
- Sifers RN "." Nat. Struct. Mol. Biol.. 2004 Feb;11(2):108-9. Pubmed PMID:
- Termine D, Wu Y, Liu Y, Sifers RN "." Methods. 2005 Apr;35(4):348-53. Pubmed PMID:
- Mast SW, Diekman K, Karaveg K, Davis A, Sifers RN, Moremen KW "." Glycobiology. 2005 Apr;15(4):421-36. Pubmed PMID:
- Wu Y, Termine DJ, Swulius MT, Moremen KW, Sifers RN "." J. Biol. Chem.. 2007 Feb 16;282(7):4841-9. Pubmed PMID:
- Mallya M, Phillips RL, Saldanha SA, Gooptu B, Brown SC, Termine DJ, Shirvani AM, Wu Y, Sifers RN, Abagyan R, Lomas DA "." J. Med. Chem.. 2007 Nov 1;50(22):5357-63. Pubmed PMID:
- Pan S, Wang R, Zhou X, Corvera J, Kloc M, Sifers R, Gallick GE, Lin SH, Kuang J "." EMBO J.. 2008 Aug 6;27(15):2077-90. Pubmed PMID:
- Termine DJ, Moremen KW, Sifers RN "." J. Cell. Sci.. 2009 Apr 1;122:976-84. Pubmed PMID:
- Pan S, Huang L, McPherson J, Muzny D, Rouhani F, Brantly M, Gibbs R, Sifers RN "." Hepatology. 2009 Jul;50(1):275-81. Pubmed PMID:
- Sifers RN "." Nat. Chem. Biol.. 2010 Jun;6(6):400-1. Pubmed PMID:
- Sifers RN "." Proc Am Thorac Soc. 2010 Nov;7(6):376-80. Pubmed PMID:
- Pan S, Iannotti MJ, Sifers RN "." Meth. Enzymol.. 2011;499:41290. Pubmed PMID:
- Pan S, Wang S, Utama B, Huang L, Blok N, Estes MK, Moremen KW, Sifers RN "." Mol. Biol. Cell. 2011 Aug;22(16):2810-22. Pubmed PMID:
- Pan S, Cheng X, Sifers RN "." Mol. Biol. Cell. 2013 Apr;24(8):1111-21. Pubmed PMID:
- Pan S, Cheng X, Chen H, Castro PD, Ittmann MM, Hutson AW, Zapata SK, Sifers RN. "." PLoS One. 2013 Aug 5;8(8) Pubmed PMID:
- Iannotti MJ, Figard L, Sokac AM, Sifers RN. "." J Biol Chem.. 2014 Apr 25;289(17):11844-11858. Pubmed PMID:
- Mamrosh JL, Lee JM, Wagner M, Stambrook PJ, Whitby RJ, Sifers RN, Wu SP, Tsai MJ, Demayo FJ, Moore DD. "." Elife. 2014 Apr 15; Pubmed PMID:
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