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[A1CR]

Lifespan gene

http://en.wikipedia.org/wiki/Hsp70 is one of the stress
proteins that helps
cells survive stress such as heat, and also is affected by
CR. From an
earlier paper, (1), it appeared that one of the isoforms of
the p53 oncogene
cousin protein called p63 affects how long cells survive
with respect to
cancer, and this correlates with HSP-70 expression in the
same cells. This
isoform is involved in cancer and lifespan. A second new
paper, (2),
appeared to demonstrate that this p63 isoform when expressed
at high level
blocks the expression of mammalian Sirt1gene that is
associated with the
longevity of mammalian cells and animals. The paper (1) is
free-full-text.

1. Wu G, Osada M, Guo Z, Fomenkov A, Begum S, Zhao M,
Upadhyay S, Xing M,
Wu F, Moon C, Westra WH, Koch WM, Mantovani R, Califano JA,
Ratovitski E,
Sidransky D, Trink B.

DeltaNp63alpha up-regulates the Hsp70 gene in human cancer.

Cancer Res. 2005 Feb 1;65(3):758-66.

PMID: 15705872

http://cancerres.aacrjournals.org/cgi/content/full/65/3/758

HSP70, a stress response protein, is known to be a
determinant of cell
death and cell transformation. We show that different
isoforms of p63 have
different transcriptional activities on hsp70 genes.
DeltaNp63alpha, an
abundantly expressed isoform of p63, activates (in vitro and
in vivo),
whereas TAp63gamma down-regulates the expression of hsp70.
We further show
that the transactivation domain at the NH(2) terminus of p63
represses,
whereas the COOH terminus activates hsp70 transcription. In
addition,
DeltaNp63alpha regulates transcription of the hsp70 gene
through its
interaction with the CCAAT binding factor and NF-Y
transcription factors
which are known to form a complex with the CCAAT box located
in the hsp70
promoter. Moreover, DeltaNp63alpha expression correlates
with HSP70
expression in all head and neck cancer cell lines. Finally,
we show
colocalization of DeltaNp63alpha and HSP70 in the epithelium
and
coexpression of both proteins in 41 primary head and neck
cancers. Our study
provides strong evidence for the physiologic association
between
DeltaNp63alpha and hsp70 in human cancer, thus further
supporting the
oncogenic potential of DeltaNp63alpha.

2. Sommer M, Poliak N, Upadhyay S, Ratovitski E, Nelkin BD,
Donehower LA,
Sidransky D.

DeltaNp63alpha Overexpression Induces Downregulation of
Sirt1 and an
Accelerated Aging Phenotype in the Mouse.

Cell Cycle. 2006 Sep 1;5(17) [Epub ahead of print]

PMID: 16940753

p63 is highly expressed in the skin and appears to be
an early marker
of keratinocyte differentiation. To examine the role of p63
in vivo, we
generated transgenic mice that overexpress DeltaNp63alpha in
the skin. These
mice exhibited an accelerated aging phenotype in the skin
characterized by
striking wound healing defects, decreased skin thickness,
decreased
subcutaneous fat tissue, hair loss, and decreased cell
proliferation. The
accelerated skin aging was accompanied by a dramatic
decrease in longevity
of the mice. We found that aging in DeltaNp63alpha
transgenic mice and other
mouse models correlated with levels of Sirt1, a mammalian
SIR2 orthologue
thought to extend the lifespan in lower species. Moreover,
increased
DeltaNp63alpha expression induced cellular senescence that
was rescued by
Sirt1. Our data suggest that DeltaNp63alpha levels may
affect aging in
mammals, at least in part, through regulation of Sirt1.