Peptide and Steroid Hormone Action

Definitions

Hormone – biologically active molecule that is released into circulation from site of synthesis and acts at a distant site

can be either hydrophilic (polypeptide hormone) or lipophilic (steroid) – biogenic amines can be either
binds specific receptor – on cell surface (hydrophilic hormones) or inside cell (lipophilic hormones)
lipophilic hormones bind carrier proteins to travel in circulation; hydrophilic hormones travel freely

cis-acting elements – DNA segments in the promoter region which bind trans-acting elements

trans-acting elements – molecules that impact downstream gene transcription when they bind cis-acting elements

Steroids and Polypeptide Hormones – Mechanisms of Transcription Activation

Q: What do steroid hormones and polypeptide hormones (at least those that bind G_s) have in common?

A: Both regulate gene transcription by communicating with core transcription complex through the same integrator (CBP)

(1) Polypeptide Hormones – receptor is unique to specific target cell

There are three classes of cell surface receptors used by polypeptide hormones:

(a) Ligand-gated Ion Channels – involved in secretion rather than transcription control
(b) Catalytic Receptors (receptor tyrosine kinases) – few hormones use these; more often assoc. with cytokines

one exception: the receptor for the polypeptide hormone insulin is a receptor tyrosine kinase

G-protein Receptors have a seven-transmembrane structure and interact with a G-protein and an effector enzyme

different G proteins have different functions: G_sactivates adenylate cyclase, G_p activate phospholipase C, etc.

Peptide hormones work fast and at low concentration since each receptor can activate multiple G-proteins (and so forth).

Mechanism of transcription activation by G_S-binding hormones:

(a) Hormone binds receptor, which interacts with G-protein (G_s) – this complex activates adenylate cyclase

(b) Adenylate cyclase converts ATP to cAMP, which activates the catalytic subunit of Protein Kinase A (PKA)

the cis-acting DNA element bound by CREB is called the cAMP response element (CRE)

(d) CREB (bound to the DNA) binds the CREB-binding protein (CBP) – and so do steroid hormones! (see below)
(e) CBP in turn interacts with pCAF to acetylate histones – DNA becomes uncoiled and can be transcribed

Note: In addition to affecting gene transcription, polypeptide hormones are also able to stimulate secretion

peptide hormones are the only known biological substance that can do this
involves activation of secretory vesicles through unknown mechanism involving Ca⁺⁺ and membrane potential
unlike transcription activation, this effect is instantaneous and stops immediately when hormone is removed

(2) Steroid Hormones – receptors exist in every nucleated cell (but cells respond differently)

Steroids are cholesterol derivatives (estrogen, androgen, progesterone, glucocorticoids, mineralcorticoids, vitamin D₃)

some non-steroids have actions similar to steroids: biogenic amines (thyroid hormone), retinoid acid derivatives (vit. A)
unlike peptide hormones, steroid hormones bind nuclear receptors that enter the nucleus and bind DNA

steroid hormone receptors are transcription factors with DNA binding, activation, and ligand binding domains

Steroid hormones work slower and require higher concentrations since each steroid molecule activates only one transcription event.

Mechanism of transcription activation by steroid hormones:

(a) Hormone binds cytosolic steroid hormone receptor, causing DNA binding region to be exposed

exception – thyroid hormone receptor always binds DNA, but binding hormone greatly increases activity

(b) Hormone-receptor complex is translocated to the nucleus, where it dimerizes and binds DNA

distal zinc finger causes receptors to dimerize, proximal zinc finger recognizes cis-acting elements on DNA

homodimerization causes binding to palindromic sequences separated by 3 nucleotides

examples: Progesterone Receptor, Glucocoritcoid R, Mineralcorticoid R, Androgen R, Estrogen R

heterodimerization causes binding to multiple sequences on DNA, each separated by 3-5 nucleotides

examples: Thyroid Receptor, Vit-D Receptor, RAR, RXR

(c) If steroid activates transcription, DNA-bound receptor binds a co-activator; this binds CREB-binding prot. (CBP)

if steroid represses transcription, receptor binds a co-receptor instead; this binds a histone deacetylase

(d) CBP interacts with pCAF to acetylate histones as above – DNA becomes uncoiled and can be transcribed

Note that both peptide hormones and steroid hormones are able to communicate with the core transcription complex through the same integrator (CBP).