A novel testicular RhoGAP-domain protein induces apoptosis.
The GTPase-activating proteins (GAPs) accelerate the hydrolysis of GTP to GDP by small GTPases. The GTPases play diverse roles in many cellular processes, including proliferation, cell motility, endocytosis, nuclear import/export, and nuclear membrane formation. Little is known about GAP-domain proteins in spermatogenesis. We isolated a novel RhoGAP domain-containing tGAP1 protein from male germ cells that exhibits unusual properties. The tGAP1 is expressed at low levels in early spermatogonia. Robust transcription initiates in midpachytene spermatocytes and continues after meiosis. The 175-kDa tGAP1 protein localizes to the cytoplasm of spermatocytes and to the cytoplasm and nucleus in spermatids. The protein contains four GAP domain-related sequences, in contrast to all other GAP proteins that harbor one such domain. No activity toward RhoA, Rac1, or Cdc42 could be detected. Results of transfection studies in various somatic cells indicated that low-level tGAP1 expression significantly slows down the cell cycle. Expression of higher levels of tGAP1 by infection of somatic cells with recombinant adenoviruses demonstrated that tGAP1 efficiently induces apoptosis, which to our knowledge is the first such demonstration for a RhoGAP protein. Based on its subcellular location in spermatids and its activity, tGAP1 may play a role in nuclear import/export.
Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
M Hossein
MH
Modarressi
Min
M
Cheng
Heide A
HA
Tarnasky
Nathalie
N
Lamarche-Vane
Dirk G
DG
de Rooij
Yibing
Y
Ruan
Frans A
FA
van der Hoorn
D000375:Aging / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D005810:Multigene Family; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D013087:Spermatids / Q000378:metabolism; D013094:Spermatozoa / Q000378:metabolism; D013737:Testis / Q000378:metabolism*; D014018:Tissue Distribution; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
D020690:GTPase-Activating Proteins; C085379:rho GTPase-activating protein; C499133:tGAP1 protein, rat; C499134:Rac1 protein, rat; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein