Margareta Wilhelm Group
Exploring the role of p73 isoforms during tumor development
Modern cancer therapy is based on treatments that trigger intrinsic cell death pathways, but the ability to evade these signals is one of the hallmarks of a tumor cell. Cancer cells usually bypass programmed cell death (apoptosis) by mutating the tumor suppressor gene TP53, which encodes the p53 protein central to the apoptotic response to DNA damage. More than 50% of human cancers have alterations in TP53, which take the form of either deletions causing an absence of the protein, or mutations that result in p53 proteins with altered activities.
The p53 protein is the prototypical member of a protein family that includes p63 and p73. These proteins share structural and functional homology, and act as transcription factors to regulate cellular proliferation, differentiation and death. In addition to full-length proteins that act as transcription factors (p53, TAp63 and TAp73) the p53, p63, and p73 genes also encode several different N-terminally truncated isoforms (deltaN) due to usage of an internal promoter. The deltaN isoforms block the transactivation activity of the full-length proteins in a dominant-negative fashion. Thus, the deltaN isoforms act like oncogenes. Furthermore, alternative splicing of C-terminal exons add additional isoforms (alpha, beta, gamma, delta etc)
Aberrant expression of the p73 locus has been observed in several types of cancers and has been correlated with chemotherapeutic failure and poor patient survival. Despite the homology between p53 and TAp73 it has been suggested that it is not loss of TAp73 but rather induction of deltaNp73 that is the tumorigenic event. We believe that the balance between p73 isoforms shifts during tumor initiation and this shift allows for escaping apoptosis, and for controlling tumor microenvironment. This is supported by our recent findings that TAp73 maintains genomic integrity and that deltaNp73 inhibits activation of the DNA damage pathway. We are specifically interested in how different p73 isoforms interacts with the DNA damage pathway. Furthermore, we are also studying the role of p73 isoforms in crucial steps of cancer development such as evasion of apoptosis, oncogene-induced senescence, and interaction with the tumor microenvironment. This will give us novel biological understanding of mechanisms occurring during tumor development and may in order prove beneficial in the development of preventive therapies, earlier diagnostic markers and better treatments.
|Aitor Bermejo Arteagabeitia||Associated|
|Ana Marin Navarro||PhD student, Graduate Student|
|Marina Stantic||Assistant professor|
|Margareta Wilhelm||Senior researcher|
|Johanna Wolfsberger||PhD student, Graduate Student|
|Astrid van der Geest||Associated|
ΔNp73 enhances HIF-1α protein stability through repression of the ECV complex.
Oncogene 2018 Apr;():
ΔNp73 regulates the expression of the multidrug-resistance genes ABCB1 and ABCB5 in breast cancer and melanoma cells - a short report.
Cell Oncol (Dordr) 2017 Dec;40(6):631-638
TAp73 suppresses tumor angiogenesis through repression of proangiogenic cytokines and HIF-1α activity.
Proc. Natl. Acad. Sci. U.S.A. 2015 Jan;112(1):220-5
JNK-NQO1 axis drives TAp73-mediated tumor suppression upon oxidative and proteasomal stress.
Cell Death Dis 2014 Oct;5():e1484
MYC proteins promote neuronal differentiation by controlling the mode of progenitor cell division.
EMBO Rep. 2014 Apr;15(4):383-91
TAp73 is required for macrophage-mediated innate immunity and the resolution of inflammatory responses.
Cell Death Differ. 2013 Feb;20(2):293-301
X-ray phase-contrast CO(2) angiography for sub-10 μm vessel imaging.
Phys Med Biol 2012 Nov;57(22):7431-41
The MYCN oncogene and differentiation in neuroblastoma.
Semin. Cancer Biol. 2011 Oct;21(4):256-66
PRIMA-1(MET)/APR-246 targets mutant forms of p53 family members p63 and p73.
Oncogene 2010 Dec;29(49):6442-51
Regulation of tumor suppressor p53 at the RNA level.
J. Mol. Med. 2010 Jul;88(7):645-52
Isoform-specific p73 knockout mice reveal a novel role for delta Np73 in the DNA damage response pathway.
Genes Dev. 2010 Mar;24(6):549-60
The p53 target Wig-1 regulates p53 mRNA stability through an AU-rich element.
Proc. Natl. Acad. Sci. U.S.A. 2009 Sep;106(37):15756-61
TAp73 regulates the spindle assembly checkpoint by modulating BubR1 activity.
Proc. Natl. Acad. Sci. U.S.A. 2009 Jan;106(3):797-802
TAp73 knockout shows genomic instability with infertility and tumor suppressor functions.
Genes Dev. 2008 Oct;22(19):2677-91