John_Parant

 

Assistant Professor

 

Education:

BS: Florida Institute Of Technology, Melbourne, Florida

Ph.D: University of Texas Graduate School of Biomedical Science, Houston, Texas

Postdoc: University of Utah, Salt Lake City, Utah

 

Research Interests:     

The overall focus of my lab is to understanding the regulation as well as cause of genomic instability in cancer and other diseases. Genomic instability is the most common hallmark of cancer, as well as the leading cause of miscarriages and birth defects. Understanding these signatures are both useful as prognostic indicators as well as therapeutic targets.

For over 20 years, I have been studying the tumor suppressor gene p53, and how it mediates the cellular response to genomic instability and cellular stress. The importance of this gene in tumorigenesis is most apparent by the fact that it is the most often inactivated gene in all cancers. In addition, Li Fraumeni Syndrome patients, which carry germline heterozygous p53 mutation/alteration, have a 50% likelihood of developing cancer by age 30, and 90% by age 60. While p53 has been studied for over 30 years, we still do not know how it suppresses tumorigenesis. Our lab utilizes both mouse and zebrafish animal models of Li Fraumeni syndrome to try to decipher the mechanism of p53 tumor suppression.

Sister chromatid cohesion (SCC) is an essential process for proper segregation of chromosomes. We have recently become involved in studying the effects that dysfunctional SCC have on embryonic development, as well as cancer predisposition. Roberts syndrome (RBS) is a rare autosomal developmental disease, that manifests in limb deformities, craniofacial defects, microcephaly, growth retardation, and mental retardation. RBS is due to homozygous inactivation of the gene ESCO2, involved in establishment of SCC during S-phase as the second strand is being synthesized. We are utilizing both zebrafish and mouse models of RBS to understand the pathogenesis of RBS and how SCC dysfunction affects human disease. We are also interested in why there is strong variability in disease severity (from prenatal lethality to asymptomatic adult individuals) amongst patient all null for Esco2. These studies are further assisted by over 70 zebrafish human disease models we have generated through our novel genome editing platform.

 We are also interested in knowing what determines the penetrance of a cancer syndrome individual. i.e. why does one LFS individual develop cancer at age 2, while another with the same mutation develops cancer at 60. Seeing that early diagnosis has have the strongest impact on patient survival, understanding this question would have great translational impact. Towards this, we have observed that mild SCC dysfunction strongly influences the timing of tumor onset. We are presently trying to understand the underlying mechanisms by which reduced SCC enhances tumor onset.

 

Key Publications:

Parant, J., Chavez-Reyes, A., Little, N.A., Yan, W., Reinke, V., Jochemsen, A.G., Lozano, G. Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a non-overlapping pathway with MDM2 to regulate p53. (2001) Nature Genetics 29(1), 92-95.

Liu G., Parant J. M., Lang G., Chau P., Chavez-Reyes A., El-Naggar A.,K.,  Multani A.,  Chang S., and Lozano G. Chromosome stability, in the absence apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice. (2004) Nature Genetics 36(1) 63-8

Lang G.A., Iwakuma T., Suh Y.A., Liu G., Rao V.A., Parant J.M., Valentin-Vega Y.A., Terzian T., Caldwell L.C., Strong L.C., El-Naggar A.K., Lozano G. Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. (2004) Cell: 119(6):861-72.

Parant J.M*., Sasai K.*, Brandt M.E., Carter J., Adams H.P., Stass S.A., Killary A.M., Katayama H., Sen S. Aurora Targeted disruption of Aurora A causes abnormal mitotic spindle assembly, chromosome misalignment and embryonic lethality. (2008) Oncogene 27(29):4122-7. *coauthors

Parant J.M., George S.A., Pryor R., Wittwer C. and Yost H.J. A rapid and efficient method of genotyping zebrafish mutants. (2008) Dev Dyn., 238(12):3168-74.

Parant J.M., George S.A., Holden J.A., and Yost H. J. Genetic modeling of Li-Fraumeni syndrome in zebrafish. (2010) Dis Model Mech., 3(1-2):45-56.

Parant J.M., Amsterdam A., Hopkins N., and Yost H.J. p53 dependent apoptosis, mitotic delay, and genomic instability in a zebrafish model of Roberts syndrome. In preparation.

 

Full Publication List:

 Pubmed  


To contact Dr. Parant:

Department of Pharmacology and Toxicology
UAB School of Medicine
1670 University Boulevard
VH 252Birmingham, AL 35294-0019
Phone: (205) 975-8469
Fax: (205) 934-8240
E-mail: Jparant@uab.edu