Maryam Jahanshahi

• Doctor of Philosophy
• Researcher at Icahn School of Medicine at Mount Sinai

Hippo signaling acts as a master regulatory pathway controlling growth, proliferation, and apoptosis and also ensures that variations in proliferation do not alter organ size. How the pathway coordinates restricting proliferation with organ size control remains a major unanswered question. Here we identify Rae1 as a highly-conserved target of the H...

Investigating Rae1 regulation by Warts/Lats and Yki/YAP. (A) The region surrounding the Lats1 consensus site (red box) in Rae1 is strongly conserved across species. Cells co-transfected with Mst1 and/or Lats1 and myc-Rae1 showed decreased Myc-Rae1 levels in the whole cell lysate (WCL) and also immunoprecipitated Rae1 (Myc-IP) as expected. Immunopre...

Rae1 modulation in proliferating cells modulates organ size. (A) qPCR indicates the reduction in relative mRNA levels of Rae1 upon RNAi using actgal4 and Rae1IRV, and the increase in Rae1 levels upon Rae1 over-expression using actgal4 and Rae102 and Rae103 transgenes. Low-level constitutive Rae1 RNAi with actgal4 led to approximately 50% reduction,...

Knockdown of Rae1 results in nuclear phenotypes. (A-B) Examples of S2 cells undergoing control RNAi stained for pHH3 (red), tubulin (green) and DAPI (blue). (C-E) S2 cells undergoing Rae1 RNAi stained for pHH3 (red), tubulin (green) and DAPI (blue). The pHH3 and tubulin staining (shown in both merge and individual channels) show significant abnorma...

Hippo over-expression organ size phenotypes are sensitive to downstream targets. (A-C) Transgenic over-expression of hpo in differentiating eye cells (GMR Hpo) is responsive to temperature. Increasing the temperature increases expression levels of Hpo, and therefore increases the severity of the phenotype. GMR Hpo eyes were small and rough at 25°C...

Hippo signaling negatively regulates pools of Rae1 at the cell membrane and in the cytoplasm. (A-A”) Transfecting FLAG-Rae1 into S2 cells shows Rae1 association with the cell periphery, cytoplasm, and nucleus. (B-B”) Co-transfecting FLAG-Rae1 with myc-Hpo into S2 cells reduced Rae1 levels, particularly at the cell periphery and cytoplasm. All image...

Loss of Rae1 results in proliferation phenotypes but not in aberrant cell size, differentiation, or survival. (A) Reduced organ size was not due to reduced cell size. Mosaic analysis using flip-out methods (hsFLP; Act>y+>gal4, UAS GFP/UAS Rae1IRV) positively labeled RNAi clones with GFP. Mosaic wing discs were dissected, dissociated, and subjected...

Rae1 regulates and genetically interacts with the mitotic cyclins. (A) wtsX1 MARCM eye discs (lane 2) show increased cyclin A and E protein levels compared to control MARCM discs (lane 1) consistent with previous reports. (B) wtsX1 MARCM eye discs (lane 2) show increased cycB protein levels compared to control MARCM discs (lane 1). Relative levels...

Hippo over-expression organ size phenotypes are sensitive to Rae1. (A-B) Mutation in hpo (right eye in A) and Mer (right eye in B) dominantly suppressed the reduced eye size and eye roughness of RNAi to Rae1 in the early eye (left eyes in A, B). (C) Control en>dcr, Rae1IRV wing (and tracing in in D-E,). (D-E) Mutations in hpo (E) and wts (E) domina...

Tissue overgrowing due to impaired Hippo kinase activity is sensitive to Rae1 levels. (A) Control wing (c5gal4/+). (B) RNAi to Rae1 (c5>Rae1IRT) causes a moderate reduction in wing size. (C) Over-expression of a kinase-dead Hpo transgene (c5>hpoKD) moderately increases wing size relative to controls (A). (D) This moderate overgrowth is suppressed b...

Reducing Rae1 suppresses overgrowth and impairs tissue survival upon reduction in Hippo signaling, but not upon over-expressing the myc oncogene or the caspase inhibitor p35. (A-B) Typically, RNAi to Mer (A, en>dcr, MerIRN) leads to less overgrowth than RNAi to the other tumor suppressor components ex, hpo, and wts. In cases where we saw less overg...

Rae1 was a strong hit from the DIVEC screen. (A) Schematic summarizing the DIVEC screen to identify novel substrates of the Hippo and Warts kinases. The Drosophila Gene Collection releases 1 and 2 were combined into pools of 12–16 clones. Pools were in vitro translated (IVT), labeling all clones with 35S methionine. Pool IVTs were incubated with tw...

The Hippo Pathway negatively regulates Rae1 downstream of Warts. (A) The predominant slower migrating Rae1 band (right lane, *) in MG132-treated S2 extracts from Rae1 and Hpo co-transfected cells (the band that predominates in Fig 1B) is decreased (arrow) when incubated in the presence of phosphatase (left lane). Mild debris is seen in left lane. (...

Rae1 regulates proliferation in osteosarcoma cell lines and Drosophila tissues. (A-B) Rae1 loss in the U2OS osteosarcoma cell line by siRNA transfection (B) reduces cell proliferation compared to controls (A). (C-D) Rae1 loss in the SJSA osteosarcoma cell line by siRNA transfection (D) reduces cell proliferation compared to controls (C). (E-G) Prol...

Reducing Rae1 suppresses overgrowth upon over-expressing the Yki oncogene. (A) Control c5gal4/+ wing at 27°C. (B) Yki over-expression (c5>YkiV5) caused wing overgrowth at 27°C. (C-D) Removing one copy of Rae1 by introducing Rae1ex28 (c5>YkiV5; Rae1ex28/+, C) or RNAi to Rae1 (c5>YkiV5; Rae1IRV/+, D) at 27°C subtly but reproducibly increased overgrow...

Genetic interactions between Hippo Pathway components and Rae1 in the eye. (DOCX)

Summary of comparisons and differences between roles and phenotypes of Rae1 and Yorkie. Table summarizes key similarities and differences of over-expressing or reducing Rae1 and Yorkie in a variety of contexts, highlighting the different mechanisms of feedback regulation exerted upon the Hippo pathway. (DOCX)

In primary brain tumors, oncogenes are frequently amplified and maintained on extrachromosomal DNA as double minutes (DM), but the underlying mechanisms remain poorly understood. We have generated a mouse model of malignant glioma based on knock-in of a mutant PDGF receptor α (PDGFRα) that is expressed in oligodendrocyte precursor cells (OPCs) afte...

Alcohol-mediated cancers represent more than 3.5% of cancer-related deaths, yet how alcohol promotes cancer is a major open question. Using Drosophila, we identified novel interactions between dietary ethanol and loss of tumor suppressor components of the Hippo Pathway. The Hippo Pathway suppresses tumors in flies and mammals by inactivating transc...

The Ras signaling pathway allows cells to translate external cues into diverse biological responses. Depending on context and the threshold reached, Ras signaling can promote growth, proliferation, differentiation, or cell survival. Failure to maintain precise control of Ras can have adverse physiological consequences. Indeed, excess Ras signaling...