The mechanism of growth-inhibitory effect of DOC-2/DAB2 in prostate cancer. Characterization of a novel GTPase-activating protein associated with N-terminal domain of DOC-2/DAB2.
DOC-2/DAB2 is a member of the disable gene family with tumor-inhibitory activity. Its down-regulation is associated with several neoplasms, and serine phosphorylation of its N terminus modulates DOC-2/DAB2's inhibitory effect on AP-1 transcriptional activity. We describe the cloning of DIP1/2, a novel gene that interacts with the N-terminal domain of DOC-2/DAB2. DIP1/2 is a novel GTPase-activating protein containing a Ras GTPase-activating protein homology domain (N terminus) and two other unique domains (i.e. 10 proline repeats and leucine zipper). Interaction between DOC-2/DAB2 and DIP1/2 is detected in normal tissues such as the brain and prostate. Altered expression of these two proteins is often detected in prostate cancer cells. Indeed, the presence of DIP1/2 effectively blocks mitogen-induced gene expression and inhibits the growth of prostate cancer. Thus, DOC-2/DAB2 and DIP1/2 appear to represent a unique negative regulatory complex that maintains cell homeostasis.
Wang
Zhi
Z
Department of Urology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9110, USA.
Tseng
Ching-Ping
CP
Pong
Rey-Chen
RC
Chen
Hong
H
McConnell
John D
JD
Navone
Nora
N
Hsieh
Jer-Tsong
JT
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D019556:COS Cells; D002455:Cell Division / Q000502:physiology*; D003001:Cloning, Molecular; D017931:DNA Primers; D018076:DNA, Complementary; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D020703:ras GTPase-Activating Proteins
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; C102885:DAB2 protein, human; C462952:DAB2IP protein, human; D017931:DNA Primers; D018076:DNA, Complementary; D020690:GTPase-Activating Proteins; D011506:Proteins; D025521:Tumor Suppressor Proteins; D020703:ras GTPase-Activating Proteins