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

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.




Characterization Of Udp-glucuronosyltransferase 2a1 (ugt2a1) Variants And Their Potential Role In Tobacco Carcinogenesis
Authors: Bushey R.T. , Chen G. , Blevins-Primeau A.S. , Krzeminski J. , Amin S. , Lazarus P. .
Source: Pharmacogenetics And Genomics, 2011 Feb; 21(2), p. 55-65.
PMID: 21164388
Related Citations

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 L.M. , Stagg T. , Lazarus P. .
Source: Molecular Cancer Research : Mcr, 2003 Apr; 1(6), p. 463-74.
PMID: 12692266
Related Citations

Glucuronidation: An Important Mechanism For Detoxification Of Benzo[a]pyrene Metabolites In Aerodigestive Tract Tissues
Authors: Zheng Z. , Fang J.L. , Lazarus P. .
Source: Drug Metabolism And Disposition: The Biological Fate Of Chemicals, 2002 Apr; 30(4), p. 397-403.
PMID: 11901093
Related Citations

Characterization of benzo(a)pyrene-trans-7,8-dihydrodiol glucuronidation by human tissue microsomes and overexpressed UDP-glucuronosyltransferase enzymes.
Authors: Fang J.L. , Beland F.A. , Doerge D.R. , Wiener D. , Guillemette C. , Marques M.M. , Lazarus P. .
Source: Cancer Research, 2002-04-01 00:00:00.0; 62(7), p. 1978-86.
PMID: 11929814
Related Citations

Tobacco Carcinogen-detoxifying Enzyme Ugt1a7 And Its Association With Orolaryngeal Cancer Risk
Authors: Zheng Z. , Park J.Y. , Guillemette C. , Schantz S.P. , Lazarus P. .
Source: Journal Of The National Cancer Institute, 2001-09-19 00:00:00.0; 93(18), p. 1411-8.
PMID: 11562393
Related Citations

Elucidation of CYP2E1 5' regulatory RsaI/Pstl allelic variants and their role in risk for oral cancer.
Authors: Liu S. , Park J.Y. , Schantz S.P. , Stern J.C. , Lazarus P. .
Source: Oral Oncology, 2001 Jul; 37(5), p. 437-45.
PMID: 11377232
Related Citations

O-Glucuronidation of the lung carcinogen 4-(methylnitrosamino)-1- (3-pyridyl)-1-butanol (NNAL) by human UDP-glucuronosyltransferases 2B7 and 1A9.
Authors: Ren Q. , Murphy S.E. , Zheng Z. , Lazarus P. .
Source: Drug Metabolism And Disposition: The Biological Fate Of Chemicals, 2000 Nov; 28(11), p. 1352-60.
PMID: 11038164
Related Citations

Metabolizing enzyme genotype and risk for upper aerodigestive tract cancer.
Authors: Lazarus P. , Park J.Y. .
Source: Oral Oncology, 2000 Sep; 36(5), p. 421-31.
PMID: 10964048
Related Citations

Role of polymorphisms in codons 143 and 160 of the O6-alkylguanine DNA alkyltransferase gene in lung cancer risk.
Authors: Kaur T.B. , Travaline J.M. , Gaughan J.P. , Richie J.P. , Stellman S.D. , Lazarus P. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2000 Mar; 9(3), p. 339-42.
PMID: 10750675
Related Citations

Comparison of GSTM polymorphisms and risk for oral cancer between African-Americans and Caucasians.
Authors: Park L.Y. , Muscat J.E. , Kaur T. , Schantz S.P. , Stern J.C. , Richie J.P. , Lazarus P. .
Source: Pharmacogenetics, 2000 Mar; 10(2), p. 123-31.
PMID: 10762000
Related Citations

Glucuronidation of the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by rat UDP-glucuronosyltransferase 2B1.
Authors: Ren Q. , Murphy S.E. , Dannenberg A.J. , Park J.Y. , Tephly T.R. , Lazarus P. .
Source: Drug Metabolism And Disposition: The Biological Fate Of Chemicals, 1999 Sep; 27(9), p. 1010-6.
PMID: 10460800
Related Citations

Association between glutathione S-transferase pi genetic polymorphisms and oral cancer risk.
Authors: Park J.Y. , Schantz S.P. , Stern J.C. , Kaur T. , Lazarus P. .
Source: Pharmacogenetics, 1999 Aug; 9(4), p. 497-504.
PMID: 10780269
Related Citations

A high prevalence of p53 mutations in pre-malignant oral erythroplakia.
Authors: Qin G.Z. , Park J.Y. , Chen S.Y. , Lazarus P. .
Source: International Journal Of Cancer, 1999-01-29 00:00:00.0; 80(3), p. 345-8.
PMID: 9935172
Related Citations

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 S.N. , Ren Q. , Schantz S.P. , Stern J.C. , Richie J.P. , Park J.Y. .
Source: Carcinogenesis, 1998 Mar; 19(3), p. 509-14.
PMID: 9525287
Related Citations

Risk of lung cancer from environmental exposures to tobacco smoke.
Authors: Muscat J.E. , Lazarus P. .
Source: Cancer Causes & Control : Ccc, 1997 Nov; 8(6), p. 929.
PMID: 9427436
Related Citations

CYP1A1 and GSTM1 polymorphisms and oral cancer risk.
Authors: Park J.Y. , Muscat J.E. , Ren Q. , Schantz S.P. , Harwick R.D. , Stern J.C. , Pike V. , Richie J.P. , Lazarus P. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 1997 Oct; 6(10), p. 791-7.
PMID: 9332761
Related Citations

Re-usable DNA template for the polymerase chain reaction.
Authors: Sheikh S.N. , Lazarus P. .
Source: Nucleic Acids Research, 1997-09-01 00:00:00.0; 25(17), p. 3537-42.
PMID: 9254716
Related Citations

P53 protein overexpression in lung adenocarcinomas in non-smokers.
Authors: Muscat J. , Citron M. , Wang C. , White A. , Lazarus P. .
Source: Oncology Reports, 1997 Jul-Aug; 4(4), p. 825-7.
PMID: 21590150
Related Citations

p53 alteration and human papilloma virus infection in paranasal sinus cancer.
Authors: Caruana S.M. , Zwiebel N. , Cocker R. , McCormick S.A. , Eberle R.C. , Lazarus P. .
Source: Cancer, 1997-04-01 00:00:00.0; 79(7), p. 1320-8.
PMID: 9083153
Related Citations

Typing of common human papilloma virus strains by multiplex PCR.
Authors: Lazarus P. , Caruana S. .
Source: Analytical Biochemistry, 1996-12-01 00:00:00.0; 243(1), p. 198-201.
PMID: 8954550
Related Citations

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 J.P. , Schantz S. .
Source: Carcinogenesis, 1996 Apr; 17(4), p. 733-9.
PMID: 8625484
Related Citations

p53 mutations in head and neck squamous cell carcinomas from Sudanese snuff (toombak) users.
Authors: Lazarus P. , Idris A.M. , Kim J. , Calcagnotto A. , Hoffmann D. .
Source: Cancer Detection And Prevention, 1996; 20(4), p. 270-8.
PMID: 8818386
Related Citations

A low incidence of p53 mutations in pre-malignant lesions of the oral cavity from non-tobacco users.
Authors: Lazarus P. , Garewal H.S. , Sciubba J. , Zwiebel N. , Calcagnotto A. , Fair A. , Schaefer S. , Richie J.P. .
Source: International Journal Of Cancer, 1995-02-08 00:00:00.0; 60(4), p. 458-63.
PMID: 7829258
Related Citations