Regulation of cell survival and apoptosis by phosphoinositide 3-kinase/Akt pathway.

Format:

Book

Thesis/Dissertation

Author/Creator:

Zhou, Honglin, 1940-

Contributor:

Pittman, Randall N., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Pharmacology.

Neurosciences.

0317.

0419.

Penn dissertations--Pharmacological sciences.

Pharmacological sciences--Penn dissertations.

Local Subjects:

Penn dissertations--Pharmacological sciences.

Pharmacological sciences--Penn dissertations.

0317.

0419.

Physical Description:

148 pages

Contained In:

Dissertation Abstracts International 61-03B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

Apoptosis plays an important role in the development and homeostasis of multicellular organisms. In the nervous system, apoptosis is required for normal development and has been implicated in the pathogenesis of various neurodegenerative diseases. Considerable evidence suggests that many signal transduction pathways regulate apoptosis and that apoptosis may represent the consequence of a disrupted balance between these pathways. Previous studies support that the phosphoinositide 3-kinase/Akt pathway represents the major survival signal within the cell. The overall goal of this thesis was to elucidate the cellular mechanisms by which the phosphoinositide 3-kinase/Akt pathway, and in particular the Akt pathway promotes cell survival. Major observations from these studies include the following: (1) C2-ceramide induces apoptosis in HMN1 motor neuron cells and decreases Akt activity, suggesting that decreased Akt kinase activity is involved in the apoptotic effects of ceramide. This possibility is further supported by studies showing that constitutively active Akt decreases C2-ceramide-induced death of HMN1 cells as well as COS-7 cells. These observations suggest that inhibition of the key anti-apoptotic kinase, Akt, may play an important role in ceramide-induced apoptosis. (2) By generating stable HMN1 lines expressing either Akt or Bcl-2, we find that both Akt and Bcl-2 inhibit ceramide-induced apoptosis. However, only Bcl-2 prevents the release of cytochrome c from mitochondria. On the other hand, active Akt inhibits cytochrome c induced caspase activation in a cell free assay while Bcl-2 has no effect. Further studies indicate that active Akt inhibits apoptosis induced by microinjection of cytochrome c. These data support that Akt promotes cell survival downstream of cytochrome c release. (3) Akt is required for p21 activated kinase (Pak) activation by Ras and PI 3-kinase. In addition, activation of Pak by Akt is independent of the small GTPases, Rac and Cdc42. Moreover, activated Pak inhibits apoptosis and increases Bad phosphorylation while kinase-dead Pak promotes apoptosis and decreases Bad phosphorylation. These data indicate that Pak is a novel effector of Akt that contribute to survival signals transduced by Akt.

Notes:

Thesis (Ph.D. in Pharmacological Sciences) -- University of Pennsylvania, 2000.

Source: Dissertation Abstracts International, Volume: 61-03, Section: B, page: 1347.

Supervisor: Randall N. Pittman.

Local Notes:

School code: 0175.

ISBN:

9780599702165

Access Restriction:

Restricted for use by site license.