Question #1: The Knudson Paradigm

Knudson paradigm of tumor suppressor gene inactivation:

Rb was first identified as a tumor suppressor as evidenced by the two hit hypothesis (the loss of one allele results in increased susceptibility to developing cancer, loss of the second allele results in the development of cancer).  However, there are many examples of cancer phenotypes that arise from tumor suppressor heterozygosity, a.k.a. haploinsufficiency, such as p53.  Additionally, tumor suppressor dosage could be regulated by factors outside of the genomic sequence itself such as post-transcriptional regulators (like microRNAs) or epigenetic mechanisms.

Do you support the continuum model of tumor suppression, why or why not (provide evidence)?  What are some challenges in studying this model and/or developing treatments based on this model?(Refer to Berger, Knudson, and Pandolfi, 2011)

Question #2: Connecting pRb and p53

As we learned in this unit, pRb and p53 are intimately connected.  We can now envision a "perfect storm" that could lead to cancer development that involves disruption of pRb control of the cell cycle and p53 control of senescence and apoptosis.  Discuss one of the pathways.  In other words, provide a possible scenario that could occur within a cell that would possibly lead to the proliferation of a neoplastic cell.  The idea of this post is to collectively (as a group) discuss several distinct signaling pathways connecting pRb and p53.  The review below provides additional details, as well as potential treatment options targeting these pathways.

Describe a signaling pathway deregulated in cancer that involves pRb and p53 as players.  Have any advancements been made in the understanding of these pathways since the provided review was written?

(Refer to Sherr and McCormick, 2002)

Question #3: Li-Fraumeni and restoring the "guardian"

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Li-Fraumeni syndrome (LFS) is characterized by a germline mutation in p53, and individuals with LFS are susceptible to a wide variety of cancers that can present in both childhood and adulthood.  At least half of LFS patients develop cancer before age 30.  In the attached review, details of Li-Fraumeni syndrome as well as associated cancers and screening methods are provided.  The end of the review briefly discusses treatment options for these patients.  Using this as a starting point, discuss a therapy you think is (or could be) effective and its role in regulating p53 (be specific). 

 Do you think therapies that restore p53 function are a plausible option after reading about the widespread pleiotropic effects of this gene?  Could these therapies be options for patients who do not have LFS, but harbor mutations in p53 (or have functional loss of p53)?

 (Refer to Sorrell et al., 2013)