p53

A central challenge in human cancer therapy is the identification of pathways that control tumor cell survival and chemosensitivity in the absence of functional p53.

In a new paper, Benjamin ORY and colleagues from the Leif Ellisen lab at the MGH and Harvard Med School Cancer center identified a new and physiologically important microRNA-related mechanism of p63/p73 cross-talk which governs the balance between pro-survival and pro-apoptotic programs in a common type of skin cancer called squamous cell carcinoma (SCC).

This type of cancer remains one of the most resistant to available chemotherapies. Many cancer therapeutic strategies are directed at restoring the function of the tumor suppressor gene p53, because when active, cells are more sensitive to the DNA damage induced by
chemotherapy. Other proteins related to p53, including p63 and p73 have also been implicated in cancer and cell sensitivity to
chemotherapy. Both p63 and p73 are overexpressed in SCC, and are thought to play a role in chemoresistance.

The researchers identified a subset of microRNA which target p73 for inhibition, including miR-193a-5p, a direct endogenous transcriptional target repressed by p63 and activated by pro-apoptotic p73 isoforms in both normal and tumor cells. Consequently, chemotherapy
treatment causes p63/p73-dependent induction of this miR, thereby limiting chemosensitivity due to miR-mediated feedback control of p73. The Boston researchers demonstrate that interrupting this feedback by inhibiting miR-193a suppresses tumor cell viability and induces dramatic chemosensitivity both in vitro and in vivo. Thus, they have identified a direct, miR-dependent regulatory circuit mediating inducible chemoresistance, whose inhibition provides a new therapeutic opportunity in p53-deficient tumors.

The researchers believe that these findings identify a pro-survival mechanism in SCC, and may highlight new therapeutic targets in the fight against cancer.

Benjamin Ory, Matthew R. Ramsey, Catherine Wilson, Douangsone D. Vadysirisack, Nicole Forster, James W. Rocco, S. Michael Rothenberg and Leif W. Ellisen. A

microRNA-dependent program controls p53-independent survival and chemosensitivity in human and murine squamous cell carcinoma. Journal of Clinical Investigation, 2011; DOI: 10.1172/JCI43897

<http://dx.doi.org/10.1172/JCI43897>

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from MedPage Today  By Crystal Phend

A potential clue — involving MicroRNA clusters — may help unlock mysteries surrounding the development, clinical course, and perhaps the prognosis of chronic lymphocytic leukemia (CLL), researchers report.

Several microRNA clusters appeared to work in a feedback circuit with the tumor protein p53 (TP53) and other genes with well-known prognostic significance in CLL, George A. Calin, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues found in a series of experiments.

This circuitry “likely underlies the pathogenesis and natural history of a major subset of human CLL,” they wrote in the Jan. 5 issue of the Journal of the American Medical Association.

Fabbri M, et al (2011) Association of a nicroRNA/TP53 feedback circuitry with pathogenesis and outcome of B-cell chronic lymphocytic leukemia JAMA 305, 59-67. [article]

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Dr. Preethi Gunaratne Wins Key Grants to Unleash Body’s Natural Cancer-fighting Agents

December 21, 2010 – Houston – Ovarian cancer is the fifth deadliest cancer among women, with about 15,000 deaths annually in the United States. The day when an ovarian cancer patient can treat her tumor with a single, painless pill instead of a toxic drug cocktail is the ultimate goal of the pioneering research of a University of Houston (UH) scientist.
Preethi Gunaratne, assistant professor in the department of biology and biochemistry, is studying a class of tiny genetic molecules known as microRNAs and pinpointing those that could unleash the body’s natural cancer-fighting agents and make chemotherapy a thing of the past. She discovered that miR-31 can specifically target and kill cancer cells that are deficient in p53, a crucial gene that guards the integrity of the genome and prevents cancer. More than half of all cancers and 90 percent of papillary serous tumors – the most common type of malignant ovarian cancer – are p53-deficient.

Additionally, she is developing a novel method to effectively deliver this treatment to the targeted cells by using an unusual carrier – nanoparticles of gold – through the work of Lalithya Jayarathne, a postdoctoral researcher in Gunaratne’s lab.  In lab tests, gold nanoparticles containing miR-31 penetrated 90 percent of targeted cells within 20 minutes, killing cancer cells three times faster than microRNAs delivered through lentiviruses, which are traditionally used in carrying gene-based treatments to diseased cells.

(read the entire release… )

Selected Publications

  • Creighton CJ, Fountain MD, Yu Z, Nagaraja AK, Zhu H, Khan M, Olokpa E, Zariff A, Gunaratne PH, Matzuk MM, Anderson ML. Molecular profiling uncovers a p53-associated role for microRNA-31 in inhibiting the proliferation of serous ovarian carcinomas and other cancers. Cancer Res 70(5), 1906-15. [abstract]
  • Greene SB, Gunaratne PH, Hammond SM, Rosen JM. (2010) A putative role for microRNA-205 in mammary epithelial cell progenitors. J Cell Sci 123(Pt 4), 606-18. [abstract]
  • Gu P, Reid JG, Gao X, Shaw CA, Creighton C, Tran PL, Zhou X, Drabek RB, Steffen DL, Hoang DM, Weiss MK, Naghavi AO, El-daye J, Khan MF, Legge GB, Wheeler DA, Gibbs RA, Miller JN, Cooney AJ, Gunaratne PH. (2008) Novel microRNA candidates and miRNA-mRNA pairs in embryonic stem (ES) cellsPLoS ONE 3(7), e2548.  [abstract]

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Reprogramming methodologies have provided multiple routes for achieving pluripotency. However, pluripotency is generally considered to be an almost singular state, with subtle differences described between induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs).

Researchers at UC Santa Barbara profiled miRNA expression levels across 49 human cell lines, including ESCs, iPSCs, differentiated cells, and cancer cell lines and found that the resulting miRNA profiles divided the iPSCs and hESCs examined into two distinct categories irrespective of the cell line origin. The miRNAs that defined these two pluripotency categories also distinguished cancer cells from differentiated cells.

Transcriptome analysis suggested that several gene sets related to p53 distinguished these categories, and overexpression of the p53-targeting miRNAs miR-92 and miR-141 in iPSCs was sufficient to change their classification status. Thus, these results suggest a subdivision of pluripotent stem cell states that is independent of their origin but related to p53 network status.

Neveu P, Kye MJ, Qi S, Buchholz DE, Clegg DO, Sahin M, Park IH, Kim KS, Daley GQ, Kornblum HI, Shraiman BI, Kosik KS. (2010) MicroRNA Profiling Reveals Two Distinct p53-Related Human Pluripotent Stem Cell States. Cell Stem Cell. 7(6), 671-81. [abstract]

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Long overshadowed by p53, its famous tumor-suppressing sibling, the p63 gene does the tougher, important job of stifling the spread of cancer to other organs. Not only does a specific form of p63 protein block metastasis, but it does so by activating the enzyme Dicer, which plays a pivotal role in the creation of microRNAs.

Researchers at MD Anderson Cancer Center show that TAp63, a p53 family member, suppresses tumorigenesis and metastasis, and coordinately regulates Dicer and miR-130b to suppress metastasis.  Additionally, modulation of expression of Dicer and miR-130b markedly affected the metastatic potential of cells lacking TAp63. TAp63 binds to and transactivates the Dicer promoter, demonstrating direct transcriptional regulation of Dicer by TAp63.

These data provide a novel understanding of the roles of TAp63 in tumour and metastasis suppression through the coordinate transcriptional regulation of Dicer and miR-130b and may have implications for the many processes regulated by miRNAs.

(Read the entire press release… )

Su X, Chakravarti D,  Cho MS, Liu L, Gi YJ, Lin YL, Leung ML, El-Naggar A, Creighton CJ, Suraokar MB, Wistuba I, Flores ER (2010) TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature 467, 986–990. [abstract]

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