The Regulation and Function of CDK5 in Cellular Senescence and Tumorigenesis.
Mao, Daqin.
2011
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Abstract: The cellular
senescence program evolved as a response to diverse forms of damage and stress.
Importantly, although senescence was considered a tissue culture phenomenon for many
years, recent in vivo studies demonstrated that cellular senescence represents a potent
failsafe mechanism against tumorigenesis, by halting aberrant proliferation of cells
harboring cancer-promoting mutations ... read morein benign lesions. Moreover, senescence can be
restored in a number of cancer cells. It is clear now, as with apoptosis, the senescence
response also contributes to the efficacy of certain anticancer agents. The atypical
cyclin-dependent kinase family member CDK5 is a postmitotic kinase whose activity is
mainly associated with proper development of the central nervous system (CNS), but
accumulating evidence suggests that CDK5 is also involved in other non-neuronal settings
and functions in a diverse range of processes, such as wound healing, migration,
apoptosis and senescence. Recent studies in our lab have shown that CDK5 is activated
during cellular senescence in both primary and tumor cells, and its activity is required
for the senescent morphology change. In the present study, we show that p35, one of the
activators of CDK5 in neurons, is required for CDK5 activation during senescence and the
expression of p35 itself is upregulated in senescing cells. In addition to the shape
change, CDK5/p35 is also required for the altered expression of senescent secretome. We
further investigated whether such changes would confer any biological or physiological
consequences, for example, on cell proliferation and tumorigenesis. Here we show that
CDK5 is required for the expression of senescence markers in murine embryonic
fibroblasts, as well as fibrosarcomas. Although acute loss of CDK5 does not affect the
proliferation of pre-senescent cells, CDK5 loss cooperates with Ras and
dominant-negative p53 (DNp53) in the transformation of mouse embryonic fibroblasts
(MEFs), as shown by an increased anchorage-independent growth of Cdk5-null cells in in
vitro soft agar assays. In vitro migration/invasion assays performed with these
transformed cells also show an increased motility and invasiveness in the Cdk5-null
MEFs. However, CDK5 loss does not accelerate tumor formation in a xenograft model using
transformed MEFs. Put together, these results suggest that although CDK5 is not directly
involved in the regulation of cell proliferation and tumor growth once the senescence
barrier is overcome, it may control cell motility and the metastatic potential of
cancerous cells. In addition, CDK5 could have profound effects on the microenvironment
and neighboring cells through its regulation of the secretome in senescent
cells.
Thesis (Ph.D.)--Tufts University, 2011.
Submitted to the Dept. of Biochemistry.
Advisors: Philip Hinds, and Amy Yee.
Committee: Philip Hinds, Amy Yee, Gavin Schnitzler, Grace Gill, and Karl Munger.
Keyword: Biology.read less - ID:
- 2v23w5768
- Component ID:
- tufts:20430
- To Cite:
- TARC Citation Guide EndNote
