The role and regulation of tumor suppressor p16INK4A in intestinal neoplasia.

Format:

Book

Thesis/Dissertation

Author/Creator:

Dai, Charlotte Yue.

Contributor:

Enders, Greg H., 1957- advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Cytology.

Genetics.

Molecular biology.

0307.

0369.

0379.

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Local Subjects:

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

0307.

0369.

0379.

Physical Description:

155 pages

Contained In:

Dissertation Abstracts International 62-02B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

The tumor suppressor p16 is a potent mediator of cell cycle arrest and it is inactivated in a broad spectrum of human cancers. However, little is known about the physiologic settings of p16 expression as well as factors that are important in regulating p16 during tumorigenesis. Since p16 expression is low in normal tissues and it does not appear to be required for development, we hypothesized that, like p53, p16 may be induced specifically in response to features of pre-neoplastic and neoplastic states. To test this hypothesis, we examined p16 expression in human colorectal tumorigenesis because it is one of the best-studied examples of multi-step carcinogenesis. Our study revealed that p16 is expressed at low to undetectable levels in normal colonic epithelium and is expressed at elevated levels in neoplastic cells from all stages of tumorigenesis. p16 is likely to be functional by several criteria. In addition, p16 expression was detected in areas of crypt architectural distortion and epithelial regeneration in ulcerative colitis, suggesting neoplastic changes are not required for p16 induction. Our findings suggest that p16 induction is not likely to be dependent on a specific mutational event, rather it may be a generalized cellular response to proliferative or oncogenic stress. Consistent with this notion, we obtained evidence that p16 can be induced in cultures of normal human epithelial cells following ionizing irradiation. To investigate how p16 may influence tumor development in the intestine, we introduced an Apc mutation into the INK4a-null mice. Preliminary findings suggest that the INK4a/ARF locus may restrain tumor development in the colon, in part, by suppressing angiogenesis.

p16 has been shown to play a role in senescence. However, it is unclear whether p16 can block cell proliferation irreversibly. Using a single cell assay, we demonstrated that p16 can initiate a durable block to cell proliferation and this state becomes independent of p16 expression, hypophosphorylation of pRb, or a strict G1 arrest. The finding that long term p16 expression is not required to impose an irreversible block to proliferation may have important clinical implications.

Notes:

Thesis (Ph.D. in Cell and Molecular Biology) -- University of Pennsylvania, 2001.

Source: Dissertation Abstracts International, Volume: 62-02, Section: B, page: 0662.

Supervisor: Greg H. Enders.

Local Notes:

School code: 0175.

ISBN:

9780493128306

Access Restriction:

Restricted for use by site license.