Molly F. Kulesz-Martin, Ph.D.
Molly F. Kulesz-Martin, Ph.D.
Director of research, Department of Dermatology
Professor and associate chair, Department of Dermatology
Professor, Department of Cell and Developmental Biology
Dermatology Research Division
Tumor Suppressor p53 Family, Epithelial Cell Carcinogenesis and Novel Targets for Molecular Therapy
Understanding oncogenic pathways in multistage carcinogenesis and translating knowledge from mouse in vitro and in vivo models to human cancer are essential to providing new prognostics and molecular therapy of epithelial cancers, the most prevalent types of human cancer. We developed mouse epithelial cell carcinogenesis lineages encompassing cell clones at various stages of tumor development from normal, initiated and benign, to malignant and metastatic tumorigenic derivatives for studies of mechanisms of inactivation of tumor suppressor and cell cycle regulatory pathways in tumors.
Professor and associate chair, Department of Dermatology
Professor, Department of Cell and Developmental Biology
Dermatology Research Division
Overview
Ph.D. Biology, University of Buffalo (SUNY), Roswell Park Cancer
Institute, 1979Tumor Suppressor p53 Family, Epithelial Cell Carcinogenesis and Novel Targets for Molecular Therapy
Understanding oncogenic pathways in multistage carcinogenesis and translating knowledge from mouse in vitro and in vivo models to human cancer are essential to providing new prognostics and molecular therapy of epithelial cancers, the most prevalent types of human cancer. We developed mouse epithelial cell carcinogenesis lineages encompassing cell clones at various stages of tumor development from normal, initiated and benign, to malignant and metastatic tumorigenic derivatives for studies of mechanisms of inactivation of tumor suppressor and cell cycle regulatory pathways in tumors.
Wild type p53 inactivation in cancer
Our laboratory is seeking mechanisms of inactivation of wild type endogenous p53 family proteins in vivo and in vitro, using novel assays of isoforms and protein partners in pre-cancer and squamous cell carcinoma (SCC). The p73 and p63 proteins are deficient in SCC and p53 lacks key phosphorylation critical to interaction with p300 and DNA. We are investigating the role of other p53 family members in tumor suppression and the importance of p53 post translational modifications in rapid cellular response to DNA damage.
RING domain protein Trim32
The Trim32 gene cloned in our laboratory from mouse pre-cancer cells and SCC belongs to a large family that includes RING domain-containing E-3 ubiquitin- and sumo- ligases such as PML and other proteins involved in human developmental disorders and cancers. We found that Trim32 is an E-3 ligase activated under stress that confers cell survival. Transgenic mice, Trim32 mutants and yeast two hybrid systems are providing clues about Trim32 substrate proteins, the role of Trim32 activation in cancer and inactivating mutation in human muscular dystrophy type 2H.
Identification of new cancer genes and targets
The microarray analysis of stages of carcinogenesis in our cloned keratinocyte tumorigenesis model has been extended to 28,000 mouse genes and ESTs. Candidate oncogenes or tumor suppressors that follow the BCR-ABL/Gleevec paradigm of early changes (causes) making the best molecular therapeutic targets are being identified and specifically manipulated (e.g. by viral vectors or siRNA) in order to restore cell death responses in SCC and uncover molecular targets for remission of SCC. A Molecular Profiling Resource of human tissues is facilitating discovery of interactive signaling pathways relevant to human cancers, including melanoma and non-melanoma skin and head and neck cancers.
Selected publications:
Journals
Albor A, El-Hizawi S, Horn EJ, Frosk P, Wrogemann K and Kulesz-Martin M. (2006) The interaction of Piasy with Trim32, an E3-ubiquitin ligase mutated in LGMD2H, promotes Piasy degradation and regulates UVB-induced keratinocyte apoptosis through NFkB modulation. J Biol Chem, 2006 Jun 30; [Epub ahead of print].
Abstract
Liu Y, Lagowski JP, Vanderbeek GE and Kulesz-Martin M. (2004) Facilitated search for specific genomic targets by p53 C-terminal basic DNA binding domain. Cancer Biol Ther, 3: 1102-1108.
Abstract
Horn EJ, Albor A, Liu Y, El-Hizawi S, Babcock M, Bowden GT, Hennings H, Lozano G, Weinberg WC and Kulesz-Martin M. (2004) RING protein Trim32 associated with anti-apoptotic and E3-ubiquitin ligase properties in skin carcinogenesis. Carcinogenesis, 25: 157-167.
Abstract Reprint
Knights CD, Liu Y and Kulesz-Martin M. (2003) Defective p53 post-translational modification required for wild type p53 inactivation in malignant epithelial cells with mdm2 gene amplification. J Biol Chem, 278: 52890-52900.
Abstract & Reprint
Wang Z, Liu Y, Mori M and Kulesz-Martin M. (2002) Gene expression profiling of initiated epidermal cells with benign or malignant tumor fates. Carcinogenesis, 23: 635-643.
Abstract
Chapters/invited reviews
Kulesz-Martin M and Liu Y. (2006) Sliding into home: Facilitated p53 search for targets by the basic DNA binding domain. Cell Death & Differ, 13:881-884, 2006.
Reprint
Kulesz-Martin M, Lagowski J, Fei S, Pelz C, Sears R, Powell MB, Halaban R and Johnson J. (2005) Keratinocyte and melanocyte carcinogenesis: p53 family protein activities and intersecting gene profiles. In: Proceedings from the Montagna Symposium on the Biology of the Skin “Keratinocyte and melanocyte signalling in skin cancers: Interacting pathways,” Oct 15-19, 2004, J Invest Dermatol Symp Proc, 10: 142-152.
Schneider B and Kulesz-Martin M. (2004) Destructive cycles: the role of genomic instability and adaptation in carcinogenesis. Carcinogenesis, 25:2033-2044.
Abstract Reprint
More publications
Our laboratory is seeking mechanisms of inactivation of wild type endogenous p53 family proteins in vivo and in vitro, using novel assays of isoforms and protein partners in pre-cancer and squamous cell carcinoma (SCC). The p73 and p63 proteins are deficient in SCC and p53 lacks key phosphorylation critical to interaction with p300 and DNA. We are investigating the role of other p53 family members in tumor suppression and the importance of p53 post translational modifications in rapid cellular response to DNA damage.
RING domain protein Trim32
The Trim32 gene cloned in our laboratory from mouse pre-cancer cells and SCC belongs to a large family that includes RING domain-containing E-3 ubiquitin- and sumo- ligases such as PML and other proteins involved in human developmental disorders and cancers. We found that Trim32 is an E-3 ligase activated under stress that confers cell survival. Transgenic mice, Trim32 mutants and yeast two hybrid systems are providing clues about Trim32 substrate proteins, the role of Trim32 activation in cancer and inactivating mutation in human muscular dystrophy type 2H.
Identification of new cancer genes and targets
The microarray analysis of stages of carcinogenesis in our cloned keratinocyte tumorigenesis model has been extended to 28,000 mouse genes and ESTs. Candidate oncogenes or tumor suppressors that follow the BCR-ABL/Gleevec paradigm of early changes (causes) making the best molecular therapeutic targets are being identified and specifically manipulated (e.g. by viral vectors or siRNA) in order to restore cell death responses in SCC and uncover molecular targets for remission of SCC. A Molecular Profiling Resource of human tissues is facilitating discovery of interactive signaling pathways relevant to human cancers, including melanoma and non-melanoma skin and head and neck cancers.
Selected publications:
Journals
Albor A, El-Hizawi S, Horn EJ, Frosk P, Wrogemann K and Kulesz-Martin M. (2006) The interaction of Piasy with Trim32, an E3-ubiquitin ligase mutated in LGMD2H, promotes Piasy degradation and regulates UVB-induced keratinocyte apoptosis through NFkB modulation. J Biol Chem, 2006 Jun 30; [Epub ahead of print].
Abstract
Liu Y, Lagowski JP, Vanderbeek GE and Kulesz-Martin M. (2004) Facilitated search for specific genomic targets by p53 C-terminal basic DNA binding domain. Cancer Biol Ther, 3: 1102-1108.
Abstract
Horn EJ, Albor A, Liu Y, El-Hizawi S, Babcock M, Bowden GT, Hennings H, Lozano G, Weinberg WC and Kulesz-Martin M. (2004) RING protein Trim32 associated with anti-apoptotic and E3-ubiquitin ligase properties in skin carcinogenesis. Carcinogenesis, 25: 157-167.
Abstract Reprint
Knights CD, Liu Y and Kulesz-Martin M. (2003) Defective p53 post-translational modification required for wild type p53 inactivation in malignant epithelial cells with mdm2 gene amplification. J Biol Chem, 278: 52890-52900.
Abstract & Reprint
Wang Z, Liu Y, Mori M and Kulesz-Martin M. (2002) Gene expression profiling of initiated epidermal cells with benign or malignant tumor fates. Carcinogenesis, 23: 635-643.
Abstract
Chapters/invited reviews
Kulesz-Martin M and Liu Y. (2006) Sliding into home: Facilitated p53 search for targets by the basic DNA binding domain. Cell Death & Differ, 13:881-884, 2006.
Reprint
Kulesz-Martin M, Lagowski J, Fei S, Pelz C, Sears R, Powell MB, Halaban R and Johnson J. (2005) Keratinocyte and melanocyte carcinogenesis: p53 family protein activities and intersecting gene profiles. In: Proceedings from the Montagna Symposium on the Biology of the Skin “Keratinocyte and melanocyte signalling in skin cancers: Interacting pathways,” Oct 15-19, 2004, J Invest Dermatol Symp Proc, 10: 142-152.
Schneider B and Kulesz-Martin M. (2004) Destructive cycles: the role of genomic instability and adaptation in carcinogenesis. Carcinogenesis, 25:2033-2044.
Abstract Reprint
More publications
Last updated: June 18, 2008 | Site maintained
by Michelle Bryant: dermatol@ohsu.edu