Post-transcriptional regulation of sex determination in Caenorhabditis elegans: widespread expression of the sex-determining gene fem-1 in both sexes.

Gaudet, Jeb; VanderElst, Ingrid; Spence, Andrew M.

doi:10.1091/mbc.7.7.1107

Cited by 50 publications

(38 citation statements)

References 77 publications

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“…It is possible that in XX animals SEL-10 binds to nuclearly localized FEM-1 and FEM-3 proteins and mediates their degradation, thereby preventing FEM protein-mediated export of TRA-1 and allowing TRA-1 to remain inside the nucleus and promote female development. A model in which SEL-10 mediates the degradation specifically of nuclearly localized FEM-1 and FEM-3 could also explain the finding that the overall level of FEM-1 protein appears to be similar in XX and X0 animals (41). In X0 animals, by contrast, SEL-10 would be prevented from binding FEM-1 and FEM-3 protein, resulting in the FEM-dependent export of TRA-1 out of the nucleus and subsequent male development (Fig.…”

Section: Discussionmentioning

confidence: 97%

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The Caenorhabditis elegans F-box protein SEL-10 promotes female development and may target FEM-1 and FEM-3 for degradation by the proteasome

Jäger

Schwartz²,

Horvitz³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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The Caenorhabditis elegans F-box protein SEL-10 and its human homolog have been proposed to regulate LIN-12 Notch signaling by targeting for ubiquitin-mediated proteasomal degradation LIN-12 Notch proteins and SEL-12 PS1 presenilins, the latter of which have been implicated in Alzheimer's disease. We found that sel-10 is the same gene as egl-41, which previously had been defined by gain-of-function mutations that semidominantly cause masculinization of the hermaphrodite soma. Our results demonstrate that mutations causing loss-of-function of sel-10 also have masculinizing activity, indicating that sel-10 functions to promote female development. Genetically, sel-10 acts upstream of the genes fem-1, fem-2, and fem-3 and downstream of her-1 and probably tra-2. When expressed in mammalian cells, SEL-10 protein coimmunoprecipitates with FEM-1, FEM-2, and FEM-3, which are required for masculinization, and FEM-1 and FEM-3 are targeted by SEL-10 for proteasomal degradation. We propose that SEL-10-mediated proteolysis of FEM-1 and FEM-3 is required for normal hermaphrodite development.C aenorhabditis elegans develops either as a self-fertilizing XX hermaphrodite or as an X0 male (1). The X-to-autosome (X͞A) ratio provides the primary sex-determining signal and specifies the activity of her (hermaphrodization)-1. Downstream of her-1, five genes [tra (transformer)-2, tra-3, fem ( feminization)-1, fem-2, and fem-3] control the activity of tra-1, the terminal, global regulator of somatic sexual fate. In XX animals, the her-1 gene, which encodes a secreted protein, is not expressed (2). The lack of her-1 expression in XX animals permits the activation of the transmembrane protein TRA-2, which blocks the functions of FEM-1 (a novel protein) (3), FEM-2 (a type 2C protein phosphatase) (4, 5), and FEM-3 (an ankyrin-repeat protein) (6), possibly by interacting directly with FEM-3 (7). This block leads to the activation of the Zn-finger DNA-binding protein TRA-1 (8). Active TRA-1 represses the transcription of genes required for male development, resulting in the formation of an animal with a female soma: a hermaphrodite (9, 10). In X0 animals, the HER-1 protein is present and inhibits TRA-2 (11, 12). The FEM proteins are, thus, relieved from negative regulation by TRA-2, resulting in the FEM-dependent inhibition of TRA-1 and subsequent male development.The gene egl (egg-laying-defective)-41 was defined by three semidominantly acting mutations, n1069, n1074, and n1077, which were identified in a screen for egg-laying-defective (Egl) hermaphrodites (13). Additional egl-41 alleles were identified in screens for mutations that suppress a semidominantly acting tra-2 mutation (e2055) (14), which cause the male-specific cephalic companion neurons (CEMs) to survive in hermaphrodites (n3717; H.T.S. and H.R.H., unpublished data) or that cause abnormalities in the sex-specific pattern of cell deaths in the ventral cord (n3854, n4041, and n4046; B. Galvin and H.R.H., unpublished results). egl-41 hermaphrodites are weakly masculinized; for exa...

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Section: Discussionmentioning

confidence: 97%

“…We propose that sel-10 promotes female development by downregulating fem-1 and fem-3 activities, which are required for male development. It has been proposed that fem-1 and fem-3 are regulated posttranscriptionally (3,(41)(42)(43). In the germline of XX animals fem-3 activity is down-regulated at the level of translation (44).…”

Section: Discussionmentioning

confidence: 99%

The Caenorhabditis elegans F-box protein SEL-10 promotes female development and may target FEM-1 and FEM-3 for degradation by the proteasome

Jäger

Schwartz²,

Horvitz³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…Their expression was verified by Western analysis of yeast lysates, prepared as in Ausubel et al (1989). Western analysis was performed as described (Gaudet et al 1996) with 12CA5 and an alkaline phosphatase-conjugated goat anti-mouse secondary antibody (GIBCO).…”

Section: Western Blottingmentioning

confidence: 99%

“…Both genetic and molecular evidence suggest that the fem genes are post-transcriptionally regulated (Doniach and Hodgkin 1984;Hodgkin 1986;Rosenquist and Kimble 1988;Ahringer and Kimble 1991;Ahringer et al 1992;Gaudet et al 1996). A simple model (Fig.…”

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confidence: 99%

Negative regulation of male development in Caenorhabditis elegans by a protein-protein interaction between TRA-2A and FEM-3

Mehra¹,

Gaudet²,

Heck³

et al. 1999

Genes & Development

102

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The tra-2 gene of the nematode Caenorhabditis elegans encodes a predicted membrane protein, TRA-2A, that promotes XX hermaphrodite development. Genetic analysis suggests that tra-2 is a negative regulator of three genes that are required for male development: fem-1, fem-2, and fem-3. We report that the carboxy-terminal region of TRA-2A interacts specifically with FEM-3 in the yeast two-hybrid system and in vitro. Consistent with the idea that FEM-3 is a target of negative regulation, we find that excess FEM-3 can overcome the feminizing effect of tra-2 and cause widespread masculinization of XX somatic tissues. In turn, we show that the masculinizing effects of excess FEM-3 can be suppressed by overproduction of the carboxy-terminal domain of TRA-2A. A FEM-3 fragment that retains TRA-2A-binding activity can masculinize fem-3(+) animals, but not fem-3 mutants, suggesting that it is possible to release and to activate endogenous FEM-3 by titrating TRA-2A. We propose that TRA-2A prevents male development by interacting directly with FEM-3 and that a balance between the opposing activities of TRA-2A and FEM-3 determines sex-specific cell fates in somatic tissues. When the balance favors FEM-3, it acts through or with the other FEM proteins to promote male cell fates.

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“…The fem1 family of proteins shows relatively high degree of sequence homology; for example, human FEM1B shares 30% amino acid identity with C. elegans fem-1 and is only six amino acid residues different from mouse Fem1b (Ventura-Holman et al, 1998; Chan et al, 1999), implying a possible conserved function for the fem1 proteins. That the sex determination pathways in mammals and C. elegans are quite different and that fem-1 protein is expressed at the same levels in both sexes (Gaudet et al, 1996), point to the existence of an unexplored function other than sex determination. Data presented in this study further support such a possibility.…”

Section: Discussionmentioning

confidence: 99%

Human FEM1B is required for Rad9 recruitment and CHK1 activation in response to replication stress

Shieh

2009

Oncogene

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Human checkpoint kinase 1 (CHK1) is an essential kinase required to preserve genome stability, and is activated by DNA replication blockage through the ataxia-telangiectasia-mutated-and-Rad3-related (ATR)/ATRIP-signaling pathway. In this report, we show that a novel CHK1-interacting protein, FEM1B (human homologue of the Caenorhabditis elegans sex determination fem1 protein), identified by a yeast two-hybrid screen, is involved in the activation of CHK1 by replication stress. Depletion of FEM1B by small interfering RNA in cancer cells impairs the activation of CHK1 kinase activity and attenuates the induction of CHK1 Ser345 phosphorylation upon replication interference. It is to be noted that, CHK2 Thr68 phosphorylation is not altered by FEM1B downregulation. By fractionation, we further demonstrated that FEM1B is able to associate with chromatin, and such association facilitates chromatin loading of the Rad9 protein. Consistently, ATR activity is poorly maintained in FEM1B knockdown cells; and FEM1B-ablated cells are as sensitive to replication block as CHK1-depleted cells. Our study has uncovered an adaptor protein FEM1B, which acts as a bridge linking CHK1 and Rad9, thus facilitating checkpoint signaling induced by replication stress.

show abstract

Post-transcriptional regulation of sex determination in Caenorhabditis elegans: widespread expression of the sex-determining gene fem-1 in both sexes.

Cited by 50 publications

References 77 publications

The Caenorhabditis elegans F-box protein SEL-10 promotes female development and may target FEM-1 and FEM-3 for degradation by the proteasome

The Caenorhabditis elegans F-box protein SEL-10 promotes female development and may target FEM-1 and FEM-3 for degradation by the proteasome

Negative regulation of male development in Caenorhabditis elegans by a protein-protein interaction between TRA-2A and FEM-3

Human FEM1B is required for Rad9 recruitment and CHK1 activation in response to replication stress

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