title: CIP2A promotes proliferation of spermatogonial progenitor cells and spermatogenesis in mice.
abstract: Protein phosphatase 2A (PP2A) is a critical regulator of protein serine/threonine phosphorylation. However, the physiological and developmental roles of different PP2A complexes are very poorly understood. Here, we show that a newly characterized PP2A inhibitory protein CIP2A is co-expressed with ki-67 and with self-renewal protein PLZF in the spermatogonial progenitor cell (SPC) population in the testis. CIP2A and PLZF expression was shown also to correlate Ki-67 expression in human testicular spermatogonia. Functionally, CIP2A mutant mouse testes exhibited smaller number of PLZF-positive SPCs and reduced sperm counts. Moreover, seminiferous tubuli cells isolated from CIP2A mutant mice showed reduced expression of Plzf and other renewal genes Oct-4 and Nanog at mRNA level. However, PLZF-deficient testes did not show altered CIP2A expression. Importantly, spermatogonia-specific restoration of CIP2A expression rescued PLZF expression and sperm production defects observed in CIP2A mutant mice. Taken together, these results reveal first physiological function for an emerging human oncoprotein CIP2A, and provide insights into maintenance of PLZF-positive progenitors. Moreover, demonstration that CIP2A expression can be systematically inhibited without severe consequences to normal mouse development and viability may have clinical relevance regarding targeting of oncogenic CIP2A for future cancer therapies.
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: Sami
authors.initials: S
authors.lastname: Ventelä
authors.forename: Christophe
authors.initials: C
authors.lastname: Côme
authors.forename: Juho-Antti
authors.initials: JA
authors.lastname: Mäkelä
authors.forename: Robin M
authors.initials: RM
authors.lastname: Hobbs
authors.forename: Leni
authors.initials: L
authors.lastname: Mannermaa
authors.forename: Markku
authors.initials: M
authors.lastname: Kallajoki
authors.forename: Edward K
authors.initials: EK
authors.lastname: Chan
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Jorma
authors.initials: J
authors.lastname: Toppari
authors.forename: Jukka
authors.initials: J
authors.lastname: Westermarck
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007150:Immunohistochemistry; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013091:Spermatogenesis / Q000235:genetics*; D013093:Spermatogonia / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D013997:Time Factors
chemical_list: D001324:Autoantigens; C573112:KIAA1524 protein, mouse; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D000075722:Promyelocytic Leukemia Zinc Finger Protein; C513267:Zbtb16 protein, mouse