OHSU

Graduate Studies Faculty

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Molly F. Kulesz-Martin, Ph.D.

Professor Cell & Developmental Biology
Director of Research Dermatology
Admin Unit: SOM-Dermatology Department
Lab Phone: 503-418-4274
Office: BH 2030
Mail Code: L468R
Programs:
Cell & Developmental Biology
Program in Molecular & Cellular Biosciences
Cancer Biology
Research Interests:
carcinogenesis p53, p73, p63 keratinocyte apoptosis epithelial solid tumors Trim32 E3 ligase molecular targets skin homeostasis psoriasis » Click here for more about Dr. Kulesz-Martin's research » PubMed Listing
Preceptor Rotations
Dr. Kulesz-Martin has not indicated availability for preceptor rotations at this time.
Faculty Mentorship
Dr. Kulesz-Martin has not indicated availability as a mentor at this time.
Profile

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.

 

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.

 

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.

 

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.

 

Selected recent publications


Liu Y, Bridges R, Wortham A, Kulesz-Martin M. NF-κB repression by PIAS3 mediated RelA SUMOylation. PLoS One. 2012;7(5):e37636. Epub 2012 May 23.