CCAR2 is a widely expressed protein involved in the regulation of a
variety of transcriptional complexes. High expression of CCAR2 correlates with
poor outcomes in a variety of human tumor types such as Squamous Cell Carcinoma
(SCC). Paradoxically, loss of Ccar2 in the mouse results in an
increased tumor burden, suggesting that CCAR2 may in fact function as a tumor
suppressor. Importantly, this tumor suppressor function is dependent on p53, a
protein that is inactivated in the vast majority of SCC tumors, leaving the role
of CCAR2 in p53-null tumors unclear. We sought to identify
p53-independent CCAR2 functions in Squamous Cell Carcinoma, and to examine its
role in tumorigenesis. We find that CCAR2 is highly over-expressed in
p53-deficient SCC cell lines compared to normal primary
keratinocytes due to increased protein stability. We identify a role for CCAR2
in promoting the stability of the transcription factors RFX1 and CREB1, which
are both required for proliferation. Finally, we demonstrate that CCAR2 is
required for proliferation in vitro and in established SCC
tumors in vivo. Our data suggest an important role for CCAR2 in
maintaining cell cycle progression and promoting SCC tumorigenesis.
In Escherichia coli, after DNA damage, the SOS response increases the transcription (and protein levels) of approximately 50 genes. As DNA repair ensues, the level of transcription returns to homeostatic levels. ClpXP and other proteases return the high levels of several SOS proteins to homeostasis. When all SOS genes are constitutively expressed and many SOS proteins are stabilized by the removal of ClpXP, microscopic analysis shows that cells filament, produce mini-cells and have branching protrusions along their length. The only SOS gene required (of 19 tested) for the cell length phenotype is recN. ClpXP or recN4174 (A552S, A553V), a mutant not recognized by ClpXP, produce filamentous cells with nucleoid partitioning defects. It is hypothesized that when produced at high levels during the SOS response, RecN interferes with nucleoid partitioning and Z-Ring function by holding together sections of the nucleoid, or sister nucleoids, providing another way to inhibit cell division.
RecN is a member of the Structural Maintenance of Chromosome (SMC) class of proteins. It can hold pieces of DNA together and is important for doublestrand break repair (DSBR). RecN is degraded by ClpXP. Overexpression of recN + in the absence of
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