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Publication Date

2017-07-24

Availability

UM campus only

Embargo Period

2017-07-24

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Cancer Biology (Medicine)

Date of Defense

2017-07-21

First Committee Member

Anthony Capobianco

Second Committee Member

Xin-Hai Pei

Third Committee Member

David Robbins

Fourth Committee Member

Julio Barredo

Fifth Committee Member

Yanbin Zhang

Abstract

Notch signaling is involved in many physiological and pathological cell processes. The aberrant activation of this pathway leads to deregulation of cell cycle and abnormal proliferation, leading to tumorigenesis in breast, colon, pancreas, etc. Although the general mechanism of Notch signaling pathway has been well established, several aspects remain unknown about the assembly of Notch transcriptional activation complex, such as other co-factors that may be involved and the role of posttranslational modifications in regulating Notch signaling, etc. Our lab previously demonstrated that NACK is a critical co-activator of Notch signaling, that binds to the Notch1 ternary complex. Herein, my study demonstrated that p300 and CBP acetylate Maml1 on residues 188K and 189K to recruit NACK to the Notch1 transcription complex to drive the recruitment of RNA polymerase II at the initiation of transcription. Notably, NACK is recruited to the ternary complexes containing Maml1 and Maml3, but not Maml2, presenting the first evidence to support the hypothesis that Notch transcriptional co-factors have selectivity for specific Notch ternary complex. Moreover, simultaneous inhibition of p300 and Notch has a synergistic effect in esophageal adenocarcinoma. In summary, this study provides a deeper mechanistic understanding of the assembly of the Notch transcriptional complex and provides the rationale and proof of concept for a combinatorial therapeutic attack on Notch-dependent cancers.

Keywords

Notch; NACK; p300

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