Molly F. Kulesz-Martin, Ph.D.
Molly F. Kulesz-Martin, Ph.D.
Director of Research, Department of Dermatology
Professor and Associate Chair of Dermatology
Professor of Cell and Developmental Biology
Dermatology Research Division
Epithelial Cell Homeostasis and 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. We are also investigating the development of the skin hyperproliferative disorder psoriasis, and how skin cell survival and skin inflammation processes contribute to this disease and promise new treatments. Our studies are likely to impact not only psoriasis but also other human diseases of the skin, as well as inflammatory diseases in other organs of the body.
Professor and Associate Chair of Dermatology
Professor of Cell and Developmental Biology
Dermatology Research Division
Overview
Ph.D. Biology, University of Buffalo (SUNY), Roswell Park Cancer
Institute, 1979Epithelial Cell Homeostasis and 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. We are also investigating the development of the skin hyperproliferative disorder psoriasis, and how skin cell survival and skin inflammation processes contribute to this disease and promise new treatments. Our studies are likely to impact not only psoriasis but also other human diseases of the skin, as well as inflammatory diseases in other organs of the body.
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 and knock-out mice, Trim32 mutants and yeast two hybrid systems are providing clues about Trim32 substrate proteins, including members of the Pias family of E-3 sumo-ligases and the p53 family, the role of Trim32 activation in cancer and inactivating mutation in human muscular dystrophy type 2H.
Trim32 and CCL20 in psoriasis
There is a self perpetuating cycle in psoriasis that disrupts epidermal homeostasis through alterations in keratinocytes (hyperproliferation, parakeratosis) and immunocytes (infiltration and activation). While it is well known that uncontrolled keratinocyte proliferation is largely driven by pro-inflammatory cytokines from the immunocytes, the functional role of keratinocytes in the recruitment and activation of immunocytes is poorly understood. We have discovered intriguing links between Trim32 (an E3 ubiquitin ligase), its substrate Piasy (an E3 SUMO ligase), and psoriasis, and hypothesize that Trim32 and Piasy are part of a positive feedback loop of CCL20 overproduction by keratinocytes and Th17 activation that contributes to the cycle of psoriasis. Initial evidence suggests that Trim32 is not simply a general marker of epidermal hyperplasia because its elevation in psoriasis, recognized as a Th17 disease, is not shared by atopic dermatitis, recognized as a Th2 cell disease, and because upregulation of CCL20 in keratinocytes responds to Th17 but not Th1 or Th2 cytokines. Ultimately, these studies may impact our understanding of the molecular mechanisms of psoriasis as distinct from atopic dermatitis and lead to rational improvement of treatment strategies for psoriasis patients.
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:
Hoot KE, Lighthall J, Han G, Lu SL, Li A, Ju W AND Kulesz-Martin M, Bottinger E, Wang XJ. (2008) Keratinocyte-specific Smad2 ablation results in increased epithelial-mesenchymal transition during skin cancer formation and progression. J Clin Invest, 118(8):2722-32.
Johnson J, Lagowski JP, Lawson S, Liu Y and Kulesz-Martin M. (2008) p73 expression modulates p63 and Mdm2 protein presence in complex with p53 family-specific DNA target sequence in squamous cell carcinogenesis. Oncogene, 2007 Nov19; [Epub ahead of print], Apr 24;27(19):2780-7.
Liu Y, Lagowski JP, Sundberg A, Sundholm A and Kulesz-Martin M. (2007) Microtubule disruption and tumor suppression by mitogen activated protein kinase phosphatase 4 in carcinoma. Cancer Res, 67(22):10711-9.
Johnson J, Lagowski JP, Sundberg A, Lawson S, Liu Y and Kulesz-Martin M. (2007) p73 loss triggers conversion to squamous cell carcinoma reversible upon reconstitution with TAp73. Cancer Res, 67:7723-7730.
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, 281(35):25850-25866.
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.
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.
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.
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.
More publications
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 and knock-out mice, Trim32 mutants and yeast two hybrid systems are providing clues about Trim32 substrate proteins, including members of the Pias family of E-3 sumo-ligases and the p53 family, the role of Trim32 activation in cancer and inactivating mutation in human muscular dystrophy type 2H.
Trim32 and CCL20 in psoriasis
There is a self perpetuating cycle in psoriasis that disrupts epidermal homeostasis through alterations in keratinocytes (hyperproliferation, parakeratosis) and immunocytes (infiltration and activation). While it is well known that uncontrolled keratinocyte proliferation is largely driven by pro-inflammatory cytokines from the immunocytes, the functional role of keratinocytes in the recruitment and activation of immunocytes is poorly understood. We have discovered intriguing links between Trim32 (an E3 ubiquitin ligase), its substrate Piasy (an E3 SUMO ligase), and psoriasis, and hypothesize that Trim32 and Piasy are part of a positive feedback loop of CCL20 overproduction by keratinocytes and Th17 activation that contributes to the cycle of psoriasis. Initial evidence suggests that Trim32 is not simply a general marker of epidermal hyperplasia because its elevation in psoriasis, recognized as a Th17 disease, is not shared by atopic dermatitis, recognized as a Th2 cell disease, and because upregulation of CCL20 in keratinocytes responds to Th17 but not Th1 or Th2 cytokines. Ultimately, these studies may impact our understanding of the molecular mechanisms of psoriasis as distinct from atopic dermatitis and lead to rational improvement of treatment strategies for psoriasis patients.
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:
Hoot KE, Lighthall J, Han G, Lu SL, Li A, Ju W AND Kulesz-Martin M, Bottinger E, Wang XJ. (2008) Keratinocyte-specific Smad2 ablation results in increased epithelial-mesenchymal transition during skin cancer formation and progression. J Clin Invest, 118(8):2722-32.
Johnson J, Lagowski JP, Lawson S, Liu Y and Kulesz-Martin M. (2008) p73 expression modulates p63 and Mdm2 protein presence in complex with p53 family-specific DNA target sequence in squamous cell carcinogenesis. Oncogene, 2007 Nov19; [Epub ahead of print], Apr 24;27(19):2780-7.
Liu Y, Lagowski JP, Sundberg A, Sundholm A and Kulesz-Martin M. (2007) Microtubule disruption and tumor suppression by mitogen activated protein kinase phosphatase 4 in carcinoma. Cancer Res, 67(22):10711-9.
Johnson J, Lagowski JP, Sundberg A, Lawson S, Liu Y and Kulesz-Martin M. (2007) p73 loss triggers conversion to squamous cell carcinoma reversible upon reconstitution with TAp73. Cancer Res, 67:7723-7730.
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, 281(35):25850-25866.
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.
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.
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.
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.
More publications