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Grant Details

Grant Number: 5R01CA059917-10 Interpret this number
Primary Investigator: Lazarus, Philip
Organization: Pennsylvania State Univ Hershey Med Ctr
Project Title: Analysis of 5'utr-Mediated Regulation of P53 Expression
Fiscal Year: 2006
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Abstract

The p53 tumor suppressor gene has been strongly implicated in the process of carcinogenesis. One of the initial cellular responses observed following exposure to DNA-damaging agents is an up-regulation of p53 protein. In preliminary studies from our laboratory, we have demonstrated that there is differential usage of p53 transcriptional start sites in normal human tissues as compared to that observed in human tumor specimens and most cell lines. p53 transcripts initiated at the P1 transcription start site are the major p53 species observed in tumor specimens and cell lines. In contrast, the majority of human p53 gene transcription in normal tissue is initiated from sites upstream of the P1 start site, with a full length P0- initiated p53 transcript detected at levels that reach approximately 50 percent of total p53 mRNA. In addition, we have demonstrated that p53 5' UTR sequences upstream of the P1 start site (between P0 and P1) present only in P0/P2-initiated p53 mRNA significantly decrease mRNA translational efficiency in a cis- regulated manner. This decrease is not observed for mRNAs containing only P1-specific p53 5' UTR sequences. This phenomenon may be an important mechanism for controlling the expression of p53 and may be an important biomarker for cellular transformation and tumorigenesis. The goal of this proposal will be to examine the mechanisms underlying the translational regulation manifested by p53 5' UTR sequences as well as the mechanisms involved in the switching of transcriptional start sites in normal versus tumor cells. Outlined in this proposal are studies designed to elucidate the exact sequences necessary for the manifestation of P0-induced translational regulation and determine whether these sequences reside in P0- versus P2-initiated mRNA. We will elucidate potential inhibitory elements present within the p53 5' UTR such as stem-loop structures or upstream UG (uAUG) condons and upstream open reading frames (uORFs), and whether potential P0- specific RNA-binding proteins play a role in this inhibition. Also proposed are studies examining the p53 flanking promoter sequences necessary for P0/P2-transcription. We will establish an in vitro system where the switch from P0/P2- to P1-initiated p53 transcripts can be modulated. This will enable us to better elucidate differences in the transcription factors and/or transcriptional machinery involved in P0/P2- versus P1-initiated p53 gene transcription and to better evaluate the conditions necessary for P0/P2-P1 transcriptional switching in vitro. Finally, we will examine this process in multiple human tissues including normal tissues from tobacco smoke-exposed versus unexposed individuals, tumor specimens as well as premalignant lesions. These studies will provide us with a better understanding of the importance of this mechanism in the carcinogenic process and help us evaluate the potential of this phenomenon as a biomarker for tumor initiation and progression.

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Publications

Differential transcription-coupled translational inhibition of human p53 expression: a potentially important mechanism of regulating p53 expression in normal versus tumor tissue.
Authors: Strudwick S, Carastro LM, Stagg T, Lazarus P
Source: Mol Cancer Res, 2003 Apr;1(6), p. 463-74.
PMID: 12692266
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Elucidation of CYP2E1 5' regulatory RsaI/Pstl allelic variants and their role in risk for oral cancer.
Authors: Liu S, Park JY, Schantz SP, Stern JC, Lazarus P
Source: Oral Oncol, 2001 Jul;37(5), p. 437-45.
PMID: 11377232
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Association between glutathione S-transferase pi genetic polymorphisms and oral cancer risk.
Authors: Park JY, Schantz SP, Stern JC, Kaur T, Lazarus P
Source: Pharmacogenetics, 1999 Aug;9(4), p. 497-504.
PMID: 10780269
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Comparison of GSTM polymorphisms and risk for oral cancer between African-Americans and Caucasians.
Authors: Park LY, Muscat JE, Kaur T, Schantz SP, Stern JC, Richie JP Jr, Lazarus P
Source: Pharmacogenetics, 2000 Mar;10(2), p. 123-31.
PMID: 10762000
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Role of polymorphisms in codons 143 and 160 of the O6-alkylguanine DNA alkyltransferase gene in lung cancer risk.
Authors: Kaur TB, Travaline JM, Gaughan JP, Richie JP Jr, Stellman SD, Lazarus P
Source: Cancer Epidemiol Biomarkers Prev, 2000 Mar;9(3), p. 339-42.
PMID: 10750675
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Glucuronidation of the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by rat UDP-glucuronosyltransferase 2B1.
Authors: Ren Q, Murphy SE, Dannenberg AJ, Park JY, Tephly TR, Lazarus P
Source: Drug Metab Dispos, 1999 Sep;27(9), p. 1010-6.
PMID: 10460800
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A high prevalence of p53 mutations in pre-malignant oral erythroplakia.
Authors: Qin GZ, Park JY, Chen SY, Lazarus P
Source: Int J Cancer, 1999 Jan 29;80(3), p. 345-8.
PMID: 9935172
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p53, but not p16 mutations in oral squamous cell carcinomas are associated with specific CYP1A1 and GSTM1 polymorphic genotypes and patient tobacco use.
Authors: Lazarus P, Sheikh SN, Ren Q, Schantz SP, Stern JC, Richie JP Jr, Park JY
Source: Carcinogenesis, 1998 Mar;19(3), p. 509-14.
PMID: 9525287
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CYP1A1 and GSTM1 polymorphisms and oral cancer risk.
Authors: Park JY, Muscat JE, Ren Q, Schantz SP, Harwick RD, Stern JC, Pike V, Richie JP Jr, Lazarus P
Source: Cancer Epidemiol Biomarkers Prev, 1997 Oct;6(10), p. 791-7.
PMID: 9332761
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Re-usable DNA template for the polymerase chain reaction.
Authors: Sheikh SN, Lazarus P
Source: Nucleic Acids Res, 1997 Sep 1;25(17), p. 3537-42.
PMID: 9254716
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p53 alteration and human papilloma virus infection in paranasal sinus cancer.
Authors: Caruana SM, Zwiebel N, Cocker R, McCormick SA, Eberle RC, Lazarus P
Source: Cancer, 1997 Apr 1;79(7), p. 1320-8.
PMID: 9083153
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Typing of common human papilloma virus strains by multiplex PCR.
Authors: Lazarus P, Caruana S
Source: Anal Biochem, 1996 Dec 1;243(1), p. 198-201.
PMID: 8954550
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Relationship between p53 mutation incidence in oral cavity squamous cell carcinomas and patient tobacco use.
Authors: Lazarus P, Stern J, Zwiebel N, Fair A, Richie JP Jr, Schantz S
Source: Carcinogenesis, 1996 Apr;17(4), p. 733-9.
PMID: 8625484
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