CSB Faculty
Olivia Pereira-Smith, Ph.D.
Professor
Worcester Polytechnic Institute, 1981
STCBM
(210) 562-5069
SMITHO@UTHSCSA.EDU
Research Interests:
The limited division of normal cells in culture is proposed as a model for cell aging. To understand the molecular and genetic basis for this loss of cell division in normal cells, we have chosen to study abnormal human cells (tumor derived, virus transformed) that have escaped from senescence and proliferate indefinitely (immortal). We have found that hybrids from fusion of various immortal cells with normal cells regain the senescent phenotype. This indicates that the phenotype of immortality is the result of recessive changes in genes regulating growth. We then fused various immortal human cells with each other. If the cell lines had immortalized through the same changes, immortal hybrids would be obtained. If different events had led to immortalization, hybrids would have limited division since the recessive (defective) genes of each cell line would be complemented by the good genes present in the other.
By this analysis we have identified four complementation groups for indefinite division. Using microcell fusion we determined that a normal human chromosome 4 can suppress the immortal phenotype in immortal cells lines assigned to group B. We then cloned the gene MORF4 as the cause of this effect. It is a member of a family of genes that are involved in chromatin remodeling and transcriptional regulation.
The MORF related genes, MRG15 and MRGX encode proteins that are present in multiple nucleoprotein complexes and the composition of other proteins in these complexes determines whether a gene promoter is activated or repressed. MRG15 has now been implicated in chromatin remodeling. It is involved in transcriptional regulation essential for cell proliferation, DNA repair, regulation of translation from RNA to protein and also RNA splicing via histone code recognition. Studies with neural stem/progenitor cells derived from brains of MRG15 null and wild type embryos and the initial published results indicate that null cells have defects in both proliferation and differentiation into neurons but not glial cells.
We are also involved in collaborative studies on telomeres and telomerase with Drs. I Rubelj, V Gorbunova and A Seluanov, and on mortalin with Drs R Wadhwa and S Kaul.
Research Techniques:
Cell culture of normal and immortal human and mouse cells, use of genetically modified mice, immunostaining and histochemistry, molecular and biochemical techniques: Southern, northern, western, immunoprecipitation, chromatin immunoprecipitation, PCR, real time PCR, plasmid constructs, adenoviral constructs.
PUBLICATIONS:
Chen M, Takano-Maruyama M, Pereira-Smith OM, Gaufo GO, Tominaga K. (2009)
MRG15, a component of HAT and HDAC complexes, is essential for proliferation and differentiation of neural precursor cells. J Neurosci Res. 2009 May 15;87(7):1522-31.
Garcia SN, Kirtane BM, Podlutsky AJ, Pereira-Smith OM, Tominaga K. (2007) Mrg15 null and heterozygous mouse embryonic fibroblasts exhibit DNA-repair defects post exposure to gamma ionizing radiation. FEBS Lett. 2007 Nov 13;581(27):5275-81. Epub 2007 Oct 18.
Jackson JG, Pereira-Smith OM. (2006) p53 Is Preferentially Recruited to the Promoters of Growth Arrest Genes p21 and GADD45 during Replicative Senescence of Normal Human Fibroblasts. Cancer Res. Sep 1;66(17):8356-60.
Wadhwa R, Takano S, Kaur K, Deocaris CC, Pereira-Smith OM, Reddel RR, Kaul SC. (2006) Upregulation of mortalin/mthsp70/Grp75 contributes to human carcinogenesis.Int J Cancer. 2006 Jun 15;118(12):2973-80.
Bowman BR, Moure CM, Kirtane BM, Welschhans RL, Tominaga K, Pereira-Smith OM, Quiocho FA. (2006) Multipurpose MRG domain involved in cell senescence and proliferation exhibits structural homology to a DNA-interacting domain.Structure. 2006 Jan;14(1):151-8.
Tominaga K, Kirtane B, Jackson JG, Ikeno Y, Ikeda T, Hawks C, Smith JR, Matzuk MM, Pereira-Smith OM (2005) MRG15 regulates embryonic development and cell proliferation. Mol Cell Biol.;25(8):2924-37.