The role of homeobox transcription factors in development, and RNA surveillance
Our laboratory primarily works on two topics: (1) transcriptional regulatory pathways that control embryonic stem cell and germ cell development in vivo, and
(2) RNA surveillance pathways that serve as quality-control mechanisms to degrade or "correct" aberrant transcripts that would otherwise express truncated proteins causing
developmental defects and/or cancer.
Homeobox Transcription Factors in Development
Homeobox genes encode transcription factors originally defined in fruit flies that have since been shown to have diverse roles in mammalian organisms. Many years ago we
identified the homeobox gene Pem by subtraction hybridization screening of cDNAs differentially expressed between two different T-cell lymphoma clones. We later discovered
that Pem (which we have since renamed Rhox5) is widely expressed in a variety of different tumors but normally its expression is restricted to specific cell types in
the embryo and in the reproductive tract.
RNA Surveillance
We are studying a highly conserved quality-control pathway called nonsense-mediated decay (NMD) that degrades aberrant transcripts harboring premature termination (nonsense) codons.
NMD is an essential quality control mechanism, as without it, truncated proteins possessing dominant-negative and deleterious gain-of-functions are generated. As evidence for its
importance, loss of Upf1, a gene essential for NMD, causes embryonic lethality in mice.
The targets of NMD - transcripts containing premature nonsense codons - are surprisingly common. One-third of disease-causing genes harbor premature nonsense codons as a
result of nonsense and frameshift mutations. Even normal genes commonly give rise to transcripts with premature nonsense codons. Some of these are aberrant transcripts derived as a
result of errors in RNA splicing, while others are functional transcripts that probably contain a stop codon in a "premature" position for regulatory reasons.
Selected Publications
Gudikote JP, Wilkinson MF (2002) T-cell receptor sequences that elicit strong down-regulation of premature termination codon-bearing transcripts. EMBO Journal
21:125-134.
Wilkinson MF, Shyu AB (2002) RNA surveillance by nuclear scanning? Nature Cell Biology 4:E144-E147.
Wang J, Hamilton JI, Carter MS, Li S, Wilkinson MF (2002) Alternatively spliced TCR mRNA induced by disruption of reading frame. Science 297:108-110.
Wang J, Chang YF, Hamilton JI, Wilkinson MF (2002) Nonsense-associated altered splicing: a frame-dependent response distinct from nonsense-mediated decay. Molecular
Cell 10:951-957.
Maclean JA 2nd, Chen MA, Wayne CM, Bruce SR, Rao M, Meistrich ML, Macleod C, Wilkinson MF (2005) Rhox: a new homeobox gene cluster. Cell 120:369-382.
Bhardwaj A, Wilkinson MF (2005) A metabolic enzyme doing double duty as a transcription factor. Bioessays. 27:467-471.
Maclean JA 2nd, Wilkinson MF (2005) Gene regulation in spermatogenesis. Current Topics in Developmental Biology 71:131-197.
Gudikote JP, Imam JS, Garcia RF, Wilkinson MF (2005) RNA splicing promotes translation and RNA surveillance. Nature Structural and Molecular Biology 12:801-809.
Rao MK, Pham J, Imam JS, MacLean JA, Murali D, Furuta Y, Sinha-Hikim AP, Wilkinson MF (2006) Tissue-specific RNAi reveals that WT1 expression in nurse cells controls
germ cell survival and spermatogenesis. Genes and Development 20:147-152.
Bruno I, Wilkinson MF (2006) P-bodies react to stress and nonsense. Cell 125:1036-1038.
Contact Information
- Miles Wilkinson, Ph.D.
- Department of Biochemistry & Molecular Biology
- The University of Texas M.D. Anderson Cancer Center
- 1515 Holcombe Blvd. - Unit 1000
- Houston, Texas 77030, U.S.A.
- Tel: (713) 563-3215
- Fax: (713) 834-6397
- E-mail: mwilkins@mdanderson.org
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