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Study of the role of cell cycle inhibitory protein p21WAF1/CIP1 and its possible regulatory mechanisms in melanoma progression

Grant number: 11/15840-9
Support type:Scholarships in Brazil - Master
Effective date (Start): March 01, 2012
Effective date (End): February 28, 2014
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Miriam Galvonas Jasiulionis
Grantee:Gabriela Nana Colaneri
Home Institution: Instituto Nacional de Farmacologia (INFAR). Universidade Federal de São Paulo (UNIFESP). São Paulo , SP, Brazil

Abstract

Cancer can be considered a disease of the cell cycle. In fact, virtually all cancers have alterations in genes involved in controlling the progression of some phase of the cell cycle. This progression is subject to a negative control that is exercised mainly by inhibitors of cyclin-dependent kinases (CKIs).Initially described as a potent CKI and therefore a negative regulator of cell cycle, p21waf1/cip1 is a protein whose expression levels are often deregulated in tumor cells. Paradoxically, its upregulation has been correlated with aggressive cancers and poor prognostic. The fact that there are few reports of coding region p21 mutations in different types of tumors associated with its possible oncogenic activities led to the questioning that this protein is thought to play other roles than those related to a classical tumor suppressor. Some authors have proposed the term "antagonistic duality" to define proteins that have opposing functions inside the cell, depending on its location and cellular context. p21waf1/cip1 seems to fit this definition, since its cytoplasmic functions have been shown to be different from their nuclear functions. p21waf1/cip1 protein can be regulated through post-translational modifications such as, for example, the phosphorylation of aminoacid residues that affect its stability and subcellular localization thus influencing its functions inside the cell. Moreover, its transcription may be regulated by epigenetic mechanisms. Since epigenetic changes are potentially reversible with the use of drugs, the study of epigenetic mechanisms involved in controlling p21waf1/cip1 expression becomes of great interest.In our laboratory, it was shown that metastatic murine melanoma cells express high levels of both messenger RNA and protein p21waf1/cip1. Melanoma is a cancer whose incidence increased in the last 50 years and although it is the rarest of skin cancers, it is noteworthy for being the most aggressive type of cancer in this organ. Its metastatic form is highly lethal, reaching 90% of cases. Given these facts, the general objective of this project is to investigate the role of protein p21waf1/cip1 along the melanoma progression. For this purpose it will be used a murine model of melanoma genesis, in which several cell lines were obtained after submitting the melanocytes melan-a to sustained stress conditions. Thus, it is expected:- Gaining a better understanding of the function of p21waf1/cip1 in melanoma progression;- Identify potential oncogenic activities for this protein;- Study the regulatory mechanisms that may be involved with changes in expression levels of p21waf1/cip1;- Provide tools and new therapeutic approaches for the treatment of melanoma