Prolactin and growth hormone aggregates in secretory granules: the need to understand the structure of the aggregate.

Prolactin and GH form reversible aggregates in the trans-Golgi lumen that become the dense cores of secretory granules. Aggregation is an economical means of sorting, because self-association removes the hormones from other possible pathways. Secretory granules containing different aggregates show different behavior, such as the reduction in stimulated release of granules containing R183H-GH compared with release of those containing wild-type hormone.

Anti-tumor effects of adenovirus containing human growth hormone sequences in a mouse model of human ovarian cancer.

Women with ovarian cancer have a low survival rate and develop resistance to chemotherapy, so new approaches to treatment are needed. We unexpectedly found administration of a replication-deficient adenovirus containing human growth hormone sequences (AdXGH) was beneficial in a mouse model of human ovarian cancer. Intraperitoneal injections of AdXGH prolonged median survival from a mean of 31 ± 1.

Aggregation and lack of secretion of most newly synthesized proinsulin in non-beta-cell lines.

Myoblasts transfected with HB10D insulin secrete more hormone than those transfected with wild-type insulin, as published previously, indicating that production of wild-type insulin is not efficient in these cells. The ability of non-beta-cells to produce insulin was examined in several cell lines. In clones of neuroendocrine GH(4)C(1) cells stably transfected with proinsulin, two thirds of (35)S-proinsulin was degraded within 3 h of synthesis, whereas (35)S-prolactin was stable.

Is there structural specificity in the reversible protein aggregates that are stored in secretory granules?

There are several steps that must occur for secretory granules to form: (1) Secretory proteins that make up the dense cores of the granules must be concentrated; (2) membrane proteins necessary for granule function must accumulate in the correct location; and (3) inappropriate membrane proteins and excess membrane must be removed. Reversible aggregation of secretory granule proteins provides a mechanism for concentrating and sorting these proteins. There is specificity in the way secretory granule proteins are treated in cells that make granules.

The tertiary structure and backbone dynamics of human prolactin.

Human prolactin is a 199-residue (23 kDa) protein closely related to growth hormone and placental lactogen with properties and functions resembling both a hormone and a cytokine. As a traditional hormone, prolactin is produced by lactotrophic cells in the pituitary and secreted into the bloodstream where it acts distally to regulate reproduction and promote lactation. Pituitary cells store prolactin in secretory granules organized around large prolactin aggregates, which are produced within the trans layer of the Golgi complex.

New GH-1 gene mutations: expanding the spectrum of causes of isolated growth hormone deficiency.

Estimates of the frequency of growth hormone deficiency (GHD) range from 1:4,000 to 1:10,000. Most cases are sporadic and presumed to be secondary to one of a wide variety of causes. However, in families with consanguinity, or when a second case occurs in the same family, a genetic cause may be suspected.

Prolonged retention after aggregation into secretory granules of human R183H-growth hormone (GH), a mutant that causes autosomal dominant GH deficiency type II.

Human R183H-GH causes autosomal dominant GH deficiency type II. Because we show here that the mutant hormone is fully bioactive, we have sought to locate an impairment in its progress through the secretory pathway as assessed by pulse chase experiments. Newly synthesized wild-type and R183H-GH were stable when expressed transiently in AtT20 cells, and both formed equivalent amounts of Lubrol-insoluble aggregates within 40 min after synthesis.

Molecular and cellular basis of isolated dominant-negative growth hormone deficiency, IGHD type II: insights on the secretory pathway of peptide hormones.

Estimates of the frequency of GH deficiency range from 1:4,000 to 1:10,000. Most cases are sporadic and presumed to be secondary to a wide variety of aetiologies. However, in families with consanguinity, or when a second case occurs in the same family, a genetic cause may be suspected.

Mechanisms for storage of prolactin and growth hormone in secretory granules.

There are three steps in the formation of secretory granules: aggregation of proteins to form the dense cores of granules, accumulation of appropriate membrane proteins necessary for function of the granules, and removal of extraneous membrane and inappropriate proteins by small vesicles. Formation of protein aggregates may be the initial step in this process, which is not well understood. Assays of aggregation of human prolactin and growth hormone in neuroendocrine cells indicate that acidic intracellular compartments are necessary, and Zn2+ and Cu2+ may facilitate aggregation through low affinity binding sites.

Aggregation of human wild-type and H27A-prolactin in cells and in solution: roles of Zn(2+), Cu(2+), and pH.

Aggregation of hormones is an important step in the formation of secretory granules that results in concentration of hormones. In transfected AtT20 cells, but not COS cells, Lubrol-insoluble aggregates of human prolactin (PRL) accumulated within 30 min after synthesis. Aggregation in AtT20 cells was reduced by incubation with 30 microM chloroquine, which neutralizes intracellular compartments, and was slowed by incubation with diethyldithiocarbamate, which chelates Cu(2+) and Zn(2+).