Relationship of the Biosynthesis of Α‐fetoprotein, Albumin, Hemopexin, and Haptoglobin to the Growth State of Fetal Rat Hepatocyte Cultures*

Sell, Stewart; Leffert, Hyam L.; Müller‐Eberhard, Ursula; Kida, Setsuko; Skelly, H.

doi:10.1111/j.1749-6632.1975.tb25401.x

Cited by 71 publications

(20 citation statements)

References 21 publications

(3 reference statements)

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“…6, 9, and 10). Because AFP is synthesized during the cell cycle G 1 and S phases, it has been hypothesized that it affects cell growth (11,12). The observation that AFP is able to bind estrogen led to the suggestion that AFP plays a role in sexual differentiation of the brain by protecting the fetus from the effects of circulating estrogen (13).…”

mentioning

confidence: 99%

Alpha-fetoprotein, the major fetal serum protein, is not essential for embryonic development but is required for female fertility

Gabant

Forrester

Nichols

et al. 2002

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

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The alpha-fetoprotein gene (Afp) is a member of a multigenic family that comprises the related genes encoding albumin, alphaalbumin, and vitamin D binding protein. The biological role of this major embryonic serum protein is unknown although numerous speculations have been made. We have used gene targeting to show that AFP is not required for embryonic development. AFP null embryos develop normally, and individually transplanted homozygous embryos can develop in an AFP-deficient microenvironment. Whereas mutant homozygous adult males are viable and fertile, AFP null females are infertile. Our analyses of these mice indicate that the defect is caused by a dysfunction of the hypothalamic͞ pituitary system, leading to anovulation.A lpha-fetoprotein (AFP) is a serum glycoprotein produced at high levels during fetal life by the liver and the visceral endoderm of the yolk sac and at lower levels by the developing gastrointestinal tract (1, 2). The protein expressed by the embryo is transferred to the maternal blood circulation, and abnormal levels of embryonic AFP in the maternal serum are indicative of spina bifida or Down's syndrome in the fetus (3, 4). The synthesis of AFP decreases dramatically after birth, and only trace amounts are detected in the adult (2). AFP expression has been shown to be regulated by transcriptional mechanisms involving a relatively large promoter (P1) and three distant enhancers (for reviews see refs. 5 and 6). More recently it has been shown that the first intron of the Afp gene contains an enhancer and an alternative promoter called P2 (7). The genes of the albumin family are linked in the mammalian genomes, and this conserved organization has been proposed to be important for the developmental expression switch of the genes of the family after birth (8). Several hypotheses have been proposed for the physiological function of AFP (for reviews see refs. 6, 9, and 10). Because AFP is synthesized during the cell cycle G 1 and S phases, it has been hypothesized that it affects cell growth (11, 12). The observation that AFP is able to bind estrogen led to the suggestion that AFP plays a role in sexual differentiation of the brain by protecting the fetus from the effects of circulating estrogen (13). In addition to binding estrogen, AFP, like albumin, is able to bind other steroids as well as endogenous and exogenous substances such as fatty acids, bilirubin, and various pharmaceutical agents, suggesting that AFP may play a general transportation role (for review see ref. 14). Moreover, because cellular internalization of the protein has been reported, AFP could also interact with cytoplasmic chaperone proteins that normally escort nuclear receptors or transcription cofactors through the cytoplasm toward organelle interfaces (15, 16). AFP has also been proposed to be one protein that protects the embryo against the maternal immune system, on the basis of the observation that addition of purified AFP into the culture of splenic or lymph node mononuclear cells exerts a suppressive effect on ant...

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mentioning

confidence: 99%

Alpha-fetoprotein, the major fetal serum protein, is not essential for embryonic development but is required for female fertility

Gabant

Forrester

Nichols

et al. 2002

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

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“…However, most studies have been performed either in vitro with adult hepatocytes or hepatoma cells or in vivo, in which a total absence of glucocorticoid in fetal development is not possible. The general problem with primary cultures of fetal hepatocytes is that they contain other cell types (32), and a variety of hormones and cofactors must be present in the culture medium to maintain the differentiated state (25).…”

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confidence: 99%

Regulation of rat liver maturation in vitro by glucocorticoids.

Chou¹,

Wan²,

Sakiyama³

1988

Mol. Cell. Biol.

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The biochemistry of liver maturation was studied by using the RLA209-15 fetal rat hepatocyte line that is temperature sensitive for maintenance of the differentiated fetal liver phenotype. At 33°C these cells were dedifferentiated; but at 40°C they were phenotypically differentiated and, like normal fetal hepatocytes, synthesized moderate levels of albumin and transferrin, high levels of authentic (69,000 and 73,000 molecular weight) rat fetal a-fetoprotein (AFP), and low levels of a 65,000-molecular-weight variant AFP. Our results indicated that administration of glucocorticoid hormones to RLA209-15 cells at 40°C induced a series of events associated with normal hepatocyte maturation; synthesis of fetal AFP was inhibited, whereas the synthesis of variant AFP, albumin, transferrin, tyrosine aminotransferase, and al-acid glycoprotein was induced.,The variant AFP was produced by RLA209-15 cells at both temperatures and was encoded by an mRNA of 1.7 kilobases (kb). The fetal AFP was encoded by an mRNA of 2.2 kb. Normal adult rat liver contained three AFP mRNAs of 2.2 (minor), 1.7, and 1.5 kb. The 1.7-kb adult liver AFP mRNA comigrated with the RNA found in RLA209-15 cells, and both directed the synthesis of a 50,000-molecular-weight precursor polypeptide of the variant AFP. Administration of glucocorticoids to RLA209-15 cells grown at 33°C stimulated synthesis of both the fetal and variant AFPs, but the levels of the 2.2-kb AFP mRNA were preferentially increased. RLA209-15 cells contained two glucocorticoid receptor mRNAs of 6.8 and 4.5 kb. The glucocorticoid-mediated maturation described above was blocked by the antiglucocorticoid RU486.

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“…32, 49)-specifically inhibits initiation of DNA synthesis in differentiated cultures of fetal rat hepatocytes (22)(23)(24)(25)(26)(27)40). Indirect in vivo evidence strongly associating VLDL (and/or its related metabolism) with suppression of hepatic G0.~ ~ S transitions also has been obtained.…”

Section: Discussionmentioning

confidence: 76%

“…However, growth regulation by glucagon is probably complex (6,27), and other factors, including prostaglandin-El, heparin production by mast cells, and alpha~-fetoprotein, also may be involved with suppression of hepatic VLDL production (27,28). In addition, fetal rat serum VLDL levels are significantly less (by 70-As yet, we have been unable to detect newly synthesized VLDL in "quiescent" fetal hepatocyte culture fluids, although active synthesis and secretion of other liver-specific proteins occurs (22,24,40). By contrast, adult hepatocyte cultures produce VLDL (D. Weinstein, unpublished observations) but do not grow (1).…”

Section: Discussionmentioning

confidence: 95%

“…6). Furthermore, release of cytotoxic-free fatty acids subsequent to cell-mediated VLDL hydrolysis is unlikely because of the presence of albumin in the culture fluids (22,40). It has not yet been determined whether the aqueous wash fraction of VLDL contains gangliosides, which also may play growth-controlling roles in other cell culture systems (3,16).…”

Section: Discussionmentioning

confidence: 99%

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Growth control of differentiated fetal rat hepatocytes in primary monolayer culture. IX. Specific inhibition of DNA synthesis initiation by very low density lipoprotein and possible significance to the problem of liver regeneration.

Leffert¹,

Weinstein²

1976

The Journal of Cell Biology

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Rat serum very low density lipoprotein (VLDL) inhibits initiation of DNA synthesis in fetal rat hepatocyte cultures; cells engaged in synthesizing DNA resist inhibition. VLDL action is specific and apparently blocks prereplicative protein synthesis. These and other results, from studies of altered blood VLDL levels and [3H]thymidine incorporation into isolated liver nuclei in 70% hepatectomized normal and mutant hyperlipoproteinemic rats, as well as from infusion studies with a "mitogenic" hormone solution, suggest that hepatic VLDL metabolism is linked to the suppression of hepatocyte proliferation.

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Relationship of the Biosynthesis of Α‐fetoprotein, Albumin, Hemopexin, and Haptoglobin to the Growth State of Fetal Rat Hepatocyte Cultures*

Cited by 71 publications

References 21 publications

Alpha-fetoprotein, the major fetal serum protein, is not essential for embryonic development but is required for female fertility

Alpha-fetoprotein, the major fetal serum protein, is not essential for embryonic development but is required for female fertility

Regulation of rat liver maturation in vitro by glucocorticoids.

Growth control of differentiated fetal rat hepatocytes in primary monolayer culture. IX. Specific inhibition of DNA synthesis initiation by very low density lipoprotein and possible significance to the problem of liver regeneration.

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