Meis1 and Prep1 homeodomain-containing transcription factors are essential for the normal embryonic development of several tissues and organs. Although they both can recruit Pbx at least for some of their biological function using the same homology region, the Meis1-Pbx and Prep1-Pbx complexes bind different DNA sequences and play opposite roles in tumorigenicity. In cancer, Meis1 has been extensively implicated in leukemia and neuroblastoma. Overexpression of Meis1 greatly shortens the latency and affects the penetrance of myeloid leukemia induced by Hox genes retroviral transduction. Furthermore, Meis1 has essential oncogenic function in all human leukemic MLL- translocation. Although, Meis1 is strongly suggested for involvement in human neuroblastoma and glioma, its function in non-hematological malignancies and solid tumors remains poorly defined. In contrast, Prep1 does not accelerate Hox-induced leukemogenesis. In fact heterozygous or homozygous Prep1-deficient mice develop tumors at high frequency. In mice, Prep1 haploinsufficiency causes spontaneous tumor formation and accelerates development of tumors in EμMyc transgenic mice. In human tumors, PREP1 is absent or downregulated in a large fraction of tumors including lung, breast and colon cancers. Therefore, Prep1 exerts tumor suppressor function in the cell by maintaining genomic stability and hence preventing neoplastic transformation. Here I show that Meis1 is involved in malignant transformation of Prep1-deficient MEFs and that this can be partially rescued by re-expression of Prep1. I demonstrate that the Pbx-interacting domain of Prep1 is involved in its tumor suppressor function. Moreover, Both Meis1 and Prep1 require Pbx1 for their oncogenic and tumorsppressive functions, respectively. Therefore Meis1 and Prep1 do compete for Pbx1 in the context of tumor development. Furthermore, I find Meis1 interacts with Ddx3x and Ddx5 RNA helicases,which is perturbed in the presence of Prep1. Together, the presented results suggest that Meis1 is a bona-fide oncogene also in non-hematic cells and that Prep1 impairs Meis1 tumorigenicity by either competing for Pbx1 or preventing its interaction with transcriptionally relevant partners.

UNRAVELING MOLECULAR MECHANISMS UNDERLYING MEIS1ONCOGENIC ACTIVITY; POSSIBLE COMPETITION WITH PREP1 / L. Dardaei Alghalandis ; supervisor: F. Blasi ; co-supervisors: S. Casola, E. Cw. So. Università degli Studi di Milano, 2013 Mar 04. 24. ciclo, Anno Accademico 2012. [10.13130/dardaei-alghalandis-leila_phd2013-03-04].

UNRAVELING MOLECULAR MECHANISMS UNDERLYING MEIS1ONCOGENIC ACTIVITY; POSSIBLE COMPETITION WITH PREP1

L. DARDAEI ALGHALANDIS
2013

Abstract

Meis1 and Prep1 homeodomain-containing transcription factors are essential for the normal embryonic development of several tissues and organs. Although they both can recruit Pbx at least for some of their biological function using the same homology region, the Meis1-Pbx and Prep1-Pbx complexes bind different DNA sequences and play opposite roles in tumorigenicity. In cancer, Meis1 has been extensively implicated in leukemia and neuroblastoma. Overexpression of Meis1 greatly shortens the latency and affects the penetrance of myeloid leukemia induced by Hox genes retroviral transduction. Furthermore, Meis1 has essential oncogenic function in all human leukemic MLL- translocation. Although, Meis1 is strongly suggested for involvement in human neuroblastoma and glioma, its function in non-hematological malignancies and solid tumors remains poorly defined. In contrast, Prep1 does not accelerate Hox-induced leukemogenesis. In fact heterozygous or homozygous Prep1-deficient mice develop tumors at high frequency. In mice, Prep1 haploinsufficiency causes spontaneous tumor formation and accelerates development of tumors in EμMyc transgenic mice. In human tumors, PREP1 is absent or downregulated in a large fraction of tumors including lung, breast and colon cancers. Therefore, Prep1 exerts tumor suppressor function in the cell by maintaining genomic stability and hence preventing neoplastic transformation. Here I show that Meis1 is involved in malignant transformation of Prep1-deficient MEFs and that this can be partially rescued by re-expression of Prep1. I demonstrate that the Pbx-interacting domain of Prep1 is involved in its tumor suppressor function. Moreover, Both Meis1 and Prep1 require Pbx1 for their oncogenic and tumorsppressive functions, respectively. Therefore Meis1 and Prep1 do compete for Pbx1 in the context of tumor development. Furthermore, I find Meis1 interacts with Ddx3x and Ddx5 RNA helicases,which is perturbed in the presence of Prep1. Together, the presented results suggest that Meis1 is a bona-fide oncogene also in non-hematic cells and that Prep1 impairs Meis1 tumorigenicity by either competing for Pbx1 or preventing its interaction with transcriptionally relevant partners.
4-mar-2013
supervisor: F. Blasi ; co-supervisors: S. Casola, E. Cw. So
English
24
2012
MOLECULAR MEDICINE (MOLECULAR ONCOLOGY AND HUMAN GENETICS)
Settore BIO/11 - Biologia Molecolare
Meis1 ; Prep1 ; RNA helicases ; Oncogene ; tumor suppressor ; tumorigenesis
BLASI, FRANCESCO BRUNO ARTURO
BLASI, FRANCESCO BRUNO ARTURO
Doctoral Thesis
Prodotti della ricerca::Tesi di dottorato
-2.0
open
Università degli Studi di Milano
info:eu-repo/semantics/doctoralThesis
1
L. DARDAEI ALGHALANDIS
UNRAVELING MOLECULAR MECHANISMS UNDERLYING MEIS1ONCOGENIC ACTIVITY; POSSIBLE COMPETITION WITH PREP1 / L. Dardaei Alghalandis ; supervisor: F. Blasi ; co-supervisors: S. Casola, E. Cw. So. Università degli Studi di Milano, 2013 Mar 04. 24. ciclo, Anno Accademico 2012. [10.13130/dardaei-alghalandis-leila_phd2013-03-04].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/219063
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