Pin1 regulates the timing of mammalian primordial germ cell proliferation

Atchison, Fawn W.; Capel, Blanche; Means, Anthony R.

doi:10.1242/dev.00584

Cited by 121 publications

(117 citation statements)

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“…In such a context, Pin1 thus represents a new therapeutic target that, alone or in combination with CDK inhibitors, may provide a means to limit cancer cell growth via negative modulation of pRb phosphorylation. In addition, it is worth noting that Pin1 KO mice develop normally; 24 this is very interesting from a therapeutic point of view. Most of the normal tissues that can develop tumors with high incidence, like prostate, lung, and colon, appear unaffected.…”

Section: Discussionmentioning

confidence: 97%

“…A reduction in Ser780 phosphorylation was evident in GFP-pRb-S608/612A mutants. (e) T98G cells were serum-starved, collected at different time points, and analyzed by WB with anti-phospho pRb-S608, -S612, and -S780, and pRb Pin1 selectively boosts pRb phosphorylation F Rizzolio et al specific shRNA directed to pRb 23,24 (Figure 6a). A cell growth curve assay illustrated that PIN1 KD cells proliferated at a lower rate than controls, whereas PIN1/RB1 double KD cells proliferated at the same rate as scrambled cells (Figure 6b).…”

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confidence: 99%

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Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1

et al. 2012

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Inactivation of the retinoblastoma protein (pRb) by phosphorylation triggers uncontrolled cell proliferation. Accordingly, activation of cyclin-dependent kinase (CDK)/cyclin complexes or downregulation of CDK inhibitors appears as a common event in human cancer. Here we show that Pin1 (protein interacting with NIMA (never in mitosis A)-1), a peptidylprolyl isomerase involved in the control of protein phosphorylation, is an essential mediator for inactivation of the pRb. Our results indicate that Pin1 controls cell proliferation by altering pRb phosphorylation without affecting CDK and protein phosphatase 1 and 2 activity. We demonstrated that Pin1 regulates tumor cell proliferation through direct interaction with the spacer domain of the pRb protein, and allows the interaction between CDK/cyclin complexes and pRb in mid/late G1. Phosphorylation of pRb Ser 608/612 is the crucial motif for Pin1 binding. We propose that Pin1 selectively boosts the switch from hypo-to hyper-phosphorylation of pRb in tumor cells. In addition, we demonstrate that the CDK pathway is responsible for the interaction of Pin1 and pRb. Prospectively, our findings therefore suggest that the synergism among CDK and Pin1 inhibitors holds great promise for targeted pharmacological treatment of cancer patients, with the possibility of reaching high effectiveness at tolerated doses. The retinoblastoma protein (pRb), the product of the RB1 gene (i.e., the tumor-suppressor gene involved in hereditary and sporadic retinoblastoma pathogenesis), is mainly responsible for the control of cell proliferation via two different mechanisms. The first is based on the interaction between pRb and different chromatin-modifying enzymes: pRb interacts with histone deacetylases (HDACs) 1, 2, and 3, histone methylase SUV39H1, and chromatin-remodeling enzymes Brg1 and Brm, thus repressing gene expression. 1 The second mechanism involves pRb controlling the cell cycle through interaction with the E2F family of transcription factors 2 in a phosphorylation-dependent way: in early and mid G1, the protein complex D-type cyclins/CDK4, 6 whereas in late G1, cyclins E(A)/CDK2 gradually phosphorylate pRb. Hyperphosphorylated pRb releases E2F transcription factors and allows the expression of genes that mediate entry into the S phase. 3 As pRb protein holds a central role in the cell cycle, its inactivation is necessary for enabling cancer cell proliferation. Different mechanisms of pRb inactivation have been described, although inactivation through phosphorylation is most common in human sporadic cancers. In this context, cyclin D1 overexpression induces CDK4/6 activation and thus pRb hyperphosphorylation. 4,5 In addition, the cyclindependent kinase (CDK) inhibitory partner, p16 protein (i.e.,

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Section: Discussionmentioning

confidence: 97%

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Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1

et al. 2012

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“…Ovaries were then incubated in PTC5% BSA or heat-inactivated horse serum (hiHS), for 30-60 min, before being incubated with primary antibody diluted in PT with or without 5% BSA overnight at 4 8C (anti-phosphohistone H3 (Ser28); 1:100; Upstate Cell Signaling Solutions, Charlottesville, VA, USA) to identify mitotic cells (Gurley et al 1975, Atchison et al 2003, and antimouse CD31 platelet endothelial cell adhesion molecule (PECAM-1; 1:50; BD Biosciences Pharmingen, San Jose, CA, USA), and anti-STAT3 (C20; 1:500; Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA) to identify germ cells). Ovaries were then washed in PTC1% BSA, or hiHS, for 30 min, and treated with RNase A for 30 min.…”

Section: Whole-mount Immunohistochemistry (Wmihc)mentioning

confidence: 99%

BAX regulates follicular endowment in mice

et al. 2007

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It is believed that the endowment of primordial follicles in mammalian ovaries is finite. Once follicles are depleted, infertility ensues. Thus, the size of the initial endowment has consequences for fertility and reproductive longevity. Follicular endowment is comprised of various processes that culminate with the incorporation of meiosis-arrested oocytes into primordial follicles. Apoptosis is prominent during follicular endowment, and apoptosis regulatory genes are involved in its regulation. Conflicting data exist with regard to the role of the proapoptotic Bcl-2 associated X protein (BAX) in follicular endowment. Therefore, we investigated the role of BAX during follicular endowment in embryonic and neonatal ovaries. We found that BAX is involved in regulating follicular endowment in mice. Deletion of Bax yields increased oocyte numbers in embryonic ovaries and increased follicle numbers in neonatal ovaries when compared with wild-type ovaries. Increased follicular endowment in BaxK/K ovaries is not due to enhanced germ cell viability. Further, it is not due to an increased primordial germ cell (PGC) allotment, a delay in the onset of meiosis, or altered proliferative activity of oogonia. Instead, our data suggest that the regulatory activity of BAX in follicular endowment likely occurs during PGC migration, prior to PGC colonization of the gonad.

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“…Although expression of antisense Pin1 RNA in HeLa cells has been reported to induce a cell cycle arrest with a high percentage of cells containing condensed chromatin (14), the characterization of Pin1 null mice and fibroblasts has produced evidence for a critical role of Pin1 for G 1 progression. Pin1 null primordial germ cells and MEFs grow at a slower rate compared with controls, and MEFs are impaired in cell cycle re-entry following serum deprivation (9,11,12,18). At the biochemical level, Pin1 has been suggested to positively regulate numerous proteins important for or implicated in G 1 progression, including cyclinD1, c-Jun, and ␤-catenin (10,19,20).…”

Section: Fig 5 Nima and Pina Physically Interactmentioning

confidence: 99%

PINA Is Essential for Growth and Positively Influences NIMA Function in Aspergillus nidulans

Joseph

Daigle²,

Means

2004

Journal of Biological Chemistry

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The phospho-Ser/Thr-directed prolyl-isomerase Pin1 was originally identified in vertebrate systems as a negative regulator of NIMA, a Ser/Thr protein kinase that regulates the G 2 /M transition in Aspergillus nidulans. Here we explore the physiological roles of the Pin1 orthologue, PINA, in A. nidulans and evaluate the relevance of the interaction of PINA with NIMA in this fungus. We find pinA to be an essential gene in A. nidulans. In addition, when PINA levels are reduced 50-fold the cells grow at a reduced rate. Upon germination under conditions that repress PINA expression, the cells are delayed in the interphase activation of NIMX cdc2 , whereas they traverse the other phases of the cell cycle at a similar rate to controls. These results indicate that a marked reduction of PINA results in a lengthening of G 1 . Additionally, PINA repression increases the rate at which the cells enter mitosis following release from a hydroxyurea arrest without altering the sensitivity of the fungus to agents that activate the replication or DNA damage checkpoints. In contrast to predictions based on Pin1, the physical interaction between PINA and NIMA is primarily dependent upon the prolylisomerase domain of PINA and the C-terminal 303 amino acids of NIMA. Finally, reduction of PINA levels exacerbates the nimA5 temperature-sensitive mutant, whereas overexpression of PINA decreases the severity of this mutation, results that are consistent with a positive genetic interaction between PINA and NIMA. Thus, although PINA is essential and positively regulates NIMA function, A. nidulans is most sensitive to a reduction in PINA concentration in G 1 rather than in G 2 /M.

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Pin1 regulates the timing of mammalian primordial germ cell proliferation

Cited by 121 publications

References 42 publications

Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1

Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1

BAX regulates follicular endowment in mice

PINA Is Essential for Growth and Positively Influences NIMA Function in Aspergillus nidulans

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