This proposal describes a five-year training program for the development of an academic career in CancerBiology. I have seven years experience as a molecular biologist working in cancer research and I amnowplanning to expand my skills by utilizing mouse models of solid tumors and leukemias. In the first part of theprogram, I will be mentored by Dr. Pier Paolo Pandolfi, a leading cancer biologist who has great experiencein modeling cancer in vivo and who has trained numerous independent investigators. The program will beenriched by the collaboration of Dr. C. Cordon-Cardo, Dr. S. Rafii and Dr. C. Simon. The first part of theaward will be completed at Memorial Sloan-Kettering Cancer Center, a scientific environment ofexcellencethat will provide all the resources necessary to promote the success of this Career Development Award, Research will focus on the study of the regulation of HIF-1 and tumor angiogenesis by the promyelocyticleukemia gene PML, and the fusion protein of acute promyelocytyc leukemia (API), PML-RARa. The transcription factor HIF-1 is the main regulator of cellular responses to hypoxia. HIF-1 is frequentlyupregulated in solid tumors and fosters tumor progression by promoting neoangiogenesis. Conversely, PMLis frequently lost in solid tumors. My preliminary observations indicate that PML is a negative regulator ofHIF-1. Accordingly, Pml-/- cells have higher HIF-1 activity than wild-type cells when subjected to hypoxicstimuli and Pml-/- mice have increased neoangiogenesis in response to ischemia. Finally, I have found thatPML-RARa acts as a constitutive transcriptional co-activator of HIF-1. This observation supports the novelconcept that neoangiogenesis in the bone marrow is an important process in leukemogenesis. In this proposal, I aim at answering the following questions: What is the molecular mechanism by which PML regulates HIF-1? What is the effect of PML loss in the process of neoangiogenesis in solid tumors?And, finally, is HIF activity important in the development of APL? I will address these questions in the following specific aims: 1. Elucidate the molecular mechanisms of HIF-1a regulation by PML; 2. Study the effect of PML loss on tumor angiogenesis and tumor progression invivo; 3. Study the role of HIF-1a overexpression in leukemia in mouse models of APL.The Training Program outlined in this proposal will launch my independent research career.
| Scaglioni, Pier Paolo; Rabellino, Andrea; Yung, Thomas M et al. (2012) Translation-dependent mechanisms lead to PML upregulation and mediate oncogenic K-RAS-induced cellular senescence. EMBO Mol Med 4:594-602 |
