title: Deregulation of Rb-E2F1 axis causes chromosomal instability by engaging the transactivation function of Cdc20-anaphase-promoting complex/cyclosome.
abstract: The E2F family of transcription factors regulates genes involved in various aspects of the cell cycle. Beyond the well-documented role in G1/S transition, mitotic regulation by E2F has also been reported. Proper mitotic progression is monitored by the spindle assembly checkpoint (SAC). The SAC ensures bipolar separation of chromosomes and thus prevents aneuploidy. There are limited reports on the regulation of the SAC by E2F. Our previous work identified the SAC protein Cdc20 as a novel transcriptional regulator of the mitotic ubiquitin carrier protein UbcH10. However, none of the Cdc20 transcription complex proteins have any known DNA binding domain. Here we show that an E2F1-DP1 heterodimer is involved in recruitment of the Cdc20 transcription complex to the UBCH10 promoter and in transactivation of the gene. We further show that inactivation of Rb can facilitate this transactivation process. Moreover, this E2F1-mediated regulation of UbcH10 influences mitotic progression. Deregulation of this pathway results in premature anaphase, chromosomal abnormalities, and aneuploidy. We conclude that excess E2F1 due to Rb inactivation recruits the complex of Cdc20 and the anaphase-promoting complex/cyclosome (Cdc20-APC/C) to deregulate the expression of UBCH10, leading to chromosomal instability in cancer cells.
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Somsubhra
authors.initials: S
authors.lastname: Nath
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Chowdhury
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Sanjib
authors.initials: S
authors.lastname: Dey
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Anirban
authors.initials: A
authors.lastname: Roychoudhury
authors.affiliation: Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer, Khargar, Navi Mumbai, India.
authors.forename: Abira
authors.initials: A
authors.lastname: Ganguly
authors.affiliation: Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer, Khargar, Navi Mumbai, India.
authors.forename: Dibyendu
authors.initials: D
authors.lastname: Bhattacharyya
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India susanta@iicb.res.in.
authors.forename: Susanta
authors.initials: S
authors.lastname: Roychoudhury
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D064199:Cdc20 Proteins / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D043171:Chromosomal Instability / Q000235:genetics* / Q000502:physiology; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D006801:Humans; D008938:Mitosis / Q000502:physiology; D016160:Retinoblastoma Protein / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics* / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism
chemical_list: D064199:Cdc20 Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C046288:ubiquitin carrier proteins; C105156:UBE2C protein, human; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome