The Retinoblastoma (pRB) pathway is a key tumor-suppressor pathway. It plays a pivotal role in normal development while its functional inactivation occurs in most cancers. The family of E2F factors is one of the key downstream targets of pRB and deregulated E2F activity is thought to drive proliferation in tumor cells. In contrast, less is known about novel Hippo tumor-suppressor pathway. However, recent studies in flies and in mammals suggested that Hippo pathway controls tissue homeostasis while its deregulation leads to tumorigenesis, thus, underscoring its important role in influencing the malignant state. Using a Drosophila model system, we have discovered that Hippo pathway strongly cooperates with pRB pathway in limiting cell proliferation and in maintenance of the state of terminal differentiation. Combined inactivation of both pathways gives rise to inappropriate proliferation and, surprisingly, to extensive dedifferentiation. Importantly, these two facets of a crosstalk are independent of each other and reflect distinct functions of the pRB pathway. Experiments in this proposal will use a combination of approaches and newly developed tools to define the cellular mechanisms underlying cooperation between the two pathways and to test the importance of these mechanisms in vivo.
In Aim 1, we will decipher an E2F-dependent aspect of cooperation between Hippo and RB pathways in limiting cell proliferation.
In Aim 2 we will investigate how the two pathways are integrated to maintain the differentiated state. This knowledge could eventually form a basis for manipulating the pathways and may help in designing new anticancer therapies for treating cancers.

Public Health Relevance

The focus of proposed research is to investigate the mechanisms underlying cooperation between the pRB pathway and a novel Hippo tumor suppressor pathway in control of cell proliferation and maintenance of the differentiated state in vivo. Notably, we have discovered that combined inactivation of both pathways leads to dramatic dedifferentiation. Therefore the results of the proposed research may help in designing of efficient anticancer therapies particularly those based on differentiation-induced agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM093827-03
Application #
8514010
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Gaillard, Shawn R
Project Start
2011-08-15
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$286,150
Indirect Cost
$104,006
Name
University of Illinois at Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Ariss, Majd M; Islam, Abul B M M K; Critcher, Meg et al. (2018) Single cell RNA-sequencing identifies a metabolic aspect of apoptosis in Rbf mutant. Nat Commun 9:5024
Guarner, Ana; Morris, Robert; Korenjak, Michael et al. (2017) E2F/DP Prevents Cell-Cycle Progression in Endocycling Fat Body Cells by Suppressing dATM Expression. Dev Cell 43:689-703.e5
Truscott, Mary; Islam, Abul B M M K; Frolov, Maxim V (2016) Novel regulation and functional interaction of polycistronic miRNAs. RNA 22:129-38
Zappia, Maria Paula; Frolov, Maxim V (2016) E2F function in muscle growth is necessary and sufficient for viability in Drosophila. Nat Commun 7:10509
Benevolenskaya, Elizaveta V; Frolov, Maxim V (2015) Emerging links between E2F control and mitochondrial function. Cancer Res 75:619-23
Truscott, Mary; Islam, Abul B M M K; Lightfoot, James et al. (2014) An intronic microRNA links Rb/E2F and EGFR signaling. PLoS Genet 10:e1004493
Ambrus, Aaron M; Islam, Abul B M M K; Holmes, Katherine B et al. (2013) Loss of dE2F compromises mitochondrial function. Dev Cell 27:438-51
Bayarmagnai, Battuya; Nicolay, Brandon N; Islam, Abul B M M K et al. (2012) Drosophila GAGA factor is required for full activation of the dE2f1-Yki/Sd transcriptional program. Cell Cycle 11:4191-202
Nicolay, Brandon N; Bayarmagnai, Battuya; Islam, Abul B M M K et al. (2011) Cooperation between dE2F1 and Yki/Sd defines a distinct transcriptional program necessary to bypass cell cycle exit. Genes Dev 25:323-35